Publikationen unter Beteiligung der  Ferropharm GmbH


Journal of Magnetic Resonance Imaging 2000 Nov;12(5):740-4

Age-related blood half-life of particulate contrast material: experimental results with a USPIO in rats.

Schnorr J., Taupitz M., Wagner S., Pilgrimm H., Hansel J., Hamm B.

Department of Radiology, Charite - Universitatsmedizin Berlin, Campus Charite Mitte, Berlin, Germany. matthias.taupitz@charite.de

It has been well established in the literature that phagocytic activity in animals and humans changes with age, but this phenomenon has not yet been investigated for particulate contrast agents. The present study was therefore performed to determine the effect of age on blood half-life of a superparamagnetic iron oxide blood pool contrast agent and on the velocity of its uptake in the liver and spleen of the rat by means of magnetic resonance (MR) imaging. A total of 18 rats (group A: 214-255 g, age: 45-50 days; group B: 432-563 g, age: 100-120 days) were imaged at 1.5 T using a 3D gradient-recalled echo (GRE) sequence (TR/TE 6.6/2.3 msec; alpha 25 degrees, frontal). Images were acquired before and every 3-5 minutes for up to 30 minutes after i.v. injection of 30 micromol Fe/kg of a citrate-coated superparamagnetic iron oxide-based contrast agent (VSOP-C43). Intravenous injection of VSOP-C43 resulted in a pronounced initial signal enhancement in vessels, which decreased with a half-life of 8.4 +/- 0.9 minutes in group A and of 15.9 +/- 2. 4 minutes in group B (P < 0.01). The half-life of signal decrease was 11.6 +/- 2 minutes and 19.9 +/- 4.4 minutes in the liver (P < 0. 01) and 19.6 +/- 3.1 minutes and 26.7 +/- 5.2 minutes in the spleen (not significant). The results show that the age-related phagocytic activity has a significant effect on the circulation time and velocity of uptake of a particulate MR imaging contrast agent. This fact must be taken into consideration in both the preclinical and clinical development of particulate contrast material and in the clinical application of such agents.


Journal of Magnetic Resonance Imaging 2000 Dec;12(6):905-11

New generation of monomer-stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: preclinical results in rats and rabbits.

Taupitz M., Schnorr J., Abramjuk C., Wagner S., Pilgrimm H., Hunigen H., Hamm B.

Department of Radiology, Charite - Universitatsmedizin Berlin, Campus Charite Mitte, Berlin, Germany. matthias.taupitz@charite.de

The purpose of this study was to evaluate the signal enhancement characteristics of very small superparamagnetic iron oxide particles (VSOP)-C63, a new monomer-coated, iron oxide-based magnetic resonance (MR) blood pool contrast medium with a very small particle size and optimized physical properties. Equilibrium MR angiography (MRA) of rats (thoracic and abdominal vessels) was performed at 1.5 T with a three-dimensional gradient-recalled echo (3D GRE) technique (TR/TE 6.6/2.3 msec, flip angle 25 degrees ) before and after (every 3-5 minutes up to 50 minutes) i.v. injection of VSOP-C63 [dosages: 15, 30, 45, 60, 75, and 90 micromol Fe/kg; diameter: 8 nm; relaxivities at 0.47 T: R1 = 30 l/(mmol * s); R2 = 39 l/(mmol * s)]. First-pass MRA images (3D-GRE, TR/TE 4.5/1.7 msec, flip angle 25 degrees ) were obtained with 45 micromol Fe/kg VSOP-C63 in comparison with 0.2 mmol Gd/kg of gadolinium diethylene triamine pentaacetic acid (Gd DTPA; before and every 5 seconds p.i.). MRA (3D GRE, TR/TE 4.5/1.7 msec, flip angle 25 degrees) of coronary vessels in rabbits was performed after i.v. injection of 45 micromol Fe/kg of VSOP-C63. In rats maximal S/N ratio in thoracic and abdominal arteries directly after i.v. injection of VSOP-C63 was 25 +/- 1, 43 +/- 2, 49 +/- 4, 57 +/- 3, 64 +/- 3, and 63 +/- 3 for the different dosages. Blood half-life was dose dependent (15 +/- 2, 20 +/- 3, 29 +/- 6, 37 +/- 5, 61 +/- 16, and 86 +/- 21 minutes). At a dose of 30 micromol Fe/kg even small intrarenal arteries were sharply delineated. First-pass MRA showed no significant difference in the S/N ratio between Gd-DTPA (71.5 +/- 11.5) and VSOP-C63 (65.1 +/- 18. 3). The proximal segments of the coronary arteries in rabbits were clearly depicted at a dose of 45 micromol Fe/kg. The monomer-coated, iron oxide-based contrast medium VSOP-C63 exhibits favorable properties as a blood pool agent for both equilibrium and first-pass MRA.


Radiology 2002 Jan;222(1):120-6

Coronary MR Angiography: Experimental Results with a monomer-stabilized Blood Pool Contrast Medium.

Taupitz M., Schnorr J., Wagner S., Abramjuk C., Pilgrimm H., Kivelitz D., Schink T., Hansel J., Laub G., Hunigen H., Hamm B.

Department of Radiology (M.T., J.S., S.W., D.K., J.H., B.H.) and Institute for Medical Biometry (T.S.), Charite, Medizinische Fakultat, Humboldt-Universitat zu Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany.

Department of Radiology, Charite - Universitatsmedizin Berlin, Campus Charite Mitte, Berlin, Germany. matthias.taupitz@charite.de

PURPOSE: To evaluate the signal-enhancing characteristics of monomer-coated very small superparamagnetic iron oxide (SPIO) particles used as a blood pool contrast medium for magnetic resonance (MR) angiography in the coronary arteries.

MATERIALS AND METHODS: The particles used in this study were coated with citrate as the monomer (VSOP-C91). The particles have a total diameter of 7 nm and show the following relaxivities at 0.47 T: T1, 19 L/mmol*sec(-1); T2, 29 L/mmol*sec(-1). Fifteen cardiac MR examinations were performed at 1.5 T in five pigs. Images were acquired from immediately to 35 minutes (equilibrium phase) after intravenous injection of gadopentetate dimeglumine, gadobenate dimeglumine, and the very small SPIO particles (n = 5 for each substance).

RESULTS: Immediately after administration of gadopentetate dimeglumine, gadobenate dimeglumine, and the very small SPIO particles, respectively, increases in the signal-to-noise ratio in blood were 94%, 103%, and 102% and in myocardium were 83%, 83%, and 29% (P <.05, very small SPIO particles versus the low-molecular-weight gadolinium-based compounds). Differences in the blood-to-myocardium contrast-to-noise ratio and visualization of the coronary arteries and their branches were also significant.

CONCLUSION: VSOP-C91 significantly improves visualization of the coronary arteries at MR angiography from immediately to 35 minutes after injection.


Invest Radiol 2002;37:167?177

Monomer-Coated Very Small Superparamagnetic Iron Oxide Particles as Contrast Medium for Magnetic Resonance Imaging

Preclinical In Vivo Characterization

Susanne Wagner, DVM, Jörg Schnorr, DVM, Herbert Pilgrimm, PHD, Bernd Hamm, MD and Matthias Taupitz, MD

Department of Radiology, Charite - Universitatsmedizin Berlin, Campus Charite Mitte, Berlin, Germany. matthias.taupitz@charite.de

RATIONALE AND OBJECTIVES: Preclinical in-vivo characterization of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184).

METHODS: VSOP-C184 (core diameter: 4 nm; total diameter: 8.6 nm; relaxivities in water at 0.94 T (T1) 20.1 and (T2) 37.1 l/[mmol*sec]) was investigated to determine its pharmacokinetics, efficacy, acute single dose toxicity, repeated dose toxicity, and genotoxicity.

RESULTS: The plasma elimination half-life at 0.045 mmol Fe/kg was 21.3 ± 5.5 minutes in rats and 36.1 ± 4.2 minutes in pigs, resulting in a T1-relaxation time of plasma of <100 milliseconds for 30 minutes in pigs. The particles are mainly cleared via the phagocytosing system of the liver. MR angiography at a dose of 0.045 mmol Fe/kg shows an excellent depiction of the thoracic and abdominal vasculature in rats and of the coronary arteries in pigs. The LD50 in mice is >17.9 mmol Fe/kg. A good tolerance and safety profile was found.

CONCLUSIONS: The experiments indicate, that VSOP-C184 may be a well tolerated and safe contrast medium for MR imaging that can be effectively used for MR angiography including visualization of the coronary arteries.


Invest Radiol. 2004 Jul;39(7):394-405.

Phase I clinical evaluation of citrate-coated monocrystalline very small superparamagnetic iron oxide particles as a new contrast medium for magnetic resonance imaging.

Taupitz M, Wagner S, Schnorr J, Kravec I, Pilgrimm H, Bergmann-Fritsch H, Hamm B.

Department of Radiology, Charite - Universitatsmedizin Berlin, Campus Charite Mitte, Berlin, Germany. matthias.taupitz@charite.de

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184) in a clinical phase I trial. METHODS: A total of 18 healthy subjects received either VSOP-C184 (core diameter: 4 nm; total diameter: 7 +/- 0.15 nm; relaxivities in water at 0.47 T (T1) 18.7 and (T2) 30 L/(mmol*seconds)) at doses of 0.015, 0.045, or 0.075 mmol Fe/kg (n = 5 per dose) or placebo (n = 1 per dose) as intravenous injections. Physical status and vital parameters were recorded, blood samples were collected for clinical chemistry and relaxometry (0.94 T), and urinalyses were performed before and for up to 2 weeks after administration. RESULTS: No serious adverse events occurred. The most pronounced adverse events occurred in 2 subjects of the highest dose group 45-50 minutes after injection. These were a drop in blood pressure and a drop in oxygen saturation, which were considered to be possibly drug-related and rapidly resolved without medication. Otherwise, no relevant changes in vital and laboratory parameters were observed. The parameters of iron metabolism exhibited short-term, dose-related changes. The injection of VSOP-C184 decreased T1 relaxation time of blood below 100 milliseconds for 18 minutes after a dose of 0.045 mmol [corrected] Fe/kg and for 60 minutes after 0.075 mmol [corrected] Fe/kg. CONCLUSIONS: The favorable data on the safety, tolerability, and efficacy of VSOP-C184 justify further clinical phase II and III trials as a contrast medium for MRI.


Invest Radiol. 2004 Sep;39(9):546-53.

Comparison of the iron oxide-based blood-pool contrast medium VSOP-C184 with gadopentetate dimeglumine for first-pass magnetic resonance angiography of the aorta and renal arteries in pigs.

Schnorr J, Wagner S, Abramjuk C, Wojner I, Schink T, Kroencke TJ, Schellenberger E, Hamm B, Pilgrimm H, Taupitz M.

Department of Radiology, Charite-Universitatsmedizin Berlin, Germany. joerg.schnorr@charite.de

RATIONALE AND OBJECTIVES: VSOP-C184 at a dose of 0.045 mmol Fe/kg has been shown to be an efficient blood pool contrast medium for equilibrium magnetic resonance angiography (MRA) that can be administered as a bolus. The present study was performed to determine whether VSOP-C184 is also suitable for first-pass MRA. MATERIALS AND METHODS: Fifteen MRA examinations at 1.5 T were performed in minipigs using a fast 3D fast low-angle shot (FLASH) sequence (repetition time = 4.5 ms, echo time = 1.7 ms, excitation angle = 25 degrees, matrix 256, body phased-array coil). The citrate-stabilized iron oxide preparation VSOP-C184 was investigated (total particle diameter: 7.0 +/- 0.15 nm; core size: 4 nm) and compared with gadopentetate dimeglumine (Gd-DTPA). The following doses were tested: VSOP-C184: 0.015, 0.025, and 0.035 mmol Fe/kg; Gd-DTPA: 0.1 and 0.2 mmol Gd/kg; n = 3 examinations/dose. Data were analyzed quantitatively (signal enhancement (ENH) and vessel edge definition (VED)) and qualitatively. RESULTS: First-pass MRA using the 3 doses of VSOP-C184 yielded the following ENH: aorta: 9.4 +/- 2.6; 12.31 +/- 1.2; 16.53 +/- 1.7; renal arteries: 7.6 +/- 2.2; 9.9 +/- 1.0; 13.2 +/- 0.5. The values for the 2 doses of Gd-DTPA were aorta: 12.9 +/- 1.0; 16.8 +/- 2.2; renal arteries: 11.2 +/- 1.23; 11.3 +/- 1.7. VED for the 3 doses of VSOP-C184 was aorta: 106.3 +/- 31.0; 135.3 +/- 58.8; 141.3 +/- 71.0; renal arteries: 102.2 +/- 24.3; 146.8 +/- 63.0; 126.9 +/- 37.6 and for the 2 doses of Gd-DTPA, aorta: 157.2 +/- 47.8; 164.2 +/- 36.8; renal arteries: 165.9 +/- 30.4; 170.3 +/- 38.2 respectively. The differences between VSOP-C184 and Gd-DTPA are clinically not relevant and statistically not significant (p > or = .05). Qualitative evaluation of image quality, contrast, and delineation of vessels showed the results obtained with VSOP-C184 at doses of 0.025 and 0.035 mmol Fe/kg to be similar to those of Gd-DTPA at 0.1 and 0.2 mmol Gd/kg. CONCLUSION: VSOP-C184 is suitable for first-pass MRA at doses of 0.025 and 0.035 mmol Fe/kg and thus, in addition to its blood pool characteristics, allows for selective visualization of the arteries without interfering venous signal.


Radiology. 2006 Jul;240(1):90-100. Epub 2006 May 9.

Focal liver lesions: SPIO-, gadolinium-, and ferucarbotran-enhanced dynamic T1-weighted and delayed T2-weighted MR imaging in rabbits.

Schnorr J, Wagner S, Abramjuk C, Drees R, Schink T, Schellenberger EA, Pilgrimm H, Hamm B, Taupitz M.
 
Department of Radiology, Charite-Universitatsmedizin Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany. joerg.schnorr[at]charite[dot]de

PURPOSE: To compare a superparamagnetic iron oxide (SPIO), VSOP-C184, with a gadopentetate dimeglumine with regard to signal-enhancing effects on T1-weighted dynamic magnetic resonance (MR) images and with another SPIO contrast medium with regard to signal-reducing effects on delayed T2-weighted MR images. MATERIALS AND METHODS: All experiments were approved by the responsible Animal Care Committee. Twenty rabbits (five for each contrast agent and dose) implanted with VX-2 carcinoma were imaged at 1.5 T. VSOP-C184 at 0.015 and 0.025 mmol Fe/kg was compared with gadopentetate dimeglumine at 0.15 mmol Gd/kg and ferucarbotran at 0.015 mmol Fe/kg. The imaging protocol comprised a T1-weighted dynamic gradient-echo (GRE) MR before injection and at 6-second intervals for up to 42 seconds after injection and a T2-weighted turbo spin-echo MR before and 5 minutes after injection. Images were evaluated quantitatively, and contrast media were compared by using nonparametric analysis of variance. RESULTS: At dynamic T1-weighted GRE MR imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median peak contrast-to-noise ratio (CNR) was 20.7 (25th percentile, 16.3; 75th percentile, 22.6), 24.2 (25th percentile, 19.3; 75th percentile, 28.5), 16.4 (25th percentile, 13.7; 75th percentile, 20.3), and 14.0 (25th percentile, 11.4; 75th percentile, 16.8), respectively. Both doses of VSOP-C184 yielded significantly higher CNR (P < .05) than the other two agents. At T2-weighted turbo spin-echo imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median CNR was 15.0 (25th percentile, 13.4; 75th percentile, 21.3), 15.7 (25th percentile, 14.5; 75th percentile, 19.8), 11.3 (25th percentile, 8.2; 75th percentile, 12.2), and 15.7 (25th percentile, 12.5; 75th percentile, 22.4), respectively. There was no significant difference between VSOP-C184 and ferucarbotran; both had a significantly higher CNR than did gadopentetate dimeglumine. CONCLUSION: VSOP-C184 produces higher liver-to-tumor contrast at dynamic T1-weighted imaging than does gadopentetate dimeglumine; at delayed T2-weighted imaging, the contrast is comparable to that achieved with ferucarbotran.


Invest Radiol 2007;42: 550?557

Whole-Heart Coronary Magnetic Resonance Angiograph, Contrast-Enhanced High-Resolution, Time-Resolved 3D Imaging.

Carsten Warmuth*, Jörg Schnorr*, Nicola Kaufels*, Susanne Wagner*, Herbert Pilgrimm ?, Bernd Hamm* and Matthias Taupitz*

*Department of Radiology, Charite??Universitätsmedizin Berlin, Germany; and ?Ferropharm GmbH, Forschungslabor, Teltow, Germany. E-mail: carsten.warmuth@charite.de.

Objectives:
To test the feasibility and performance of a 4D magnetic resonance coronary angiography sequence compared with conventional inversion recovery (IR) prepared gradient echo imaging.

Materials and Methods:
A 4D sequence with 100 milliseconds temporal resolution was implemented on a 1.5 T system. Five minipigs were examined after administration of very small superparamagnetic
iron oxide particles. Coronary angiographies with an isotropic resolution of 0.82 mm were performed in the pigs using 4D and IR sequences.

Results:
The 4D sequence allowed visualization of the coronary arteries, the effect of their movement and that of the entire heart without prolonging scan time. The contrast-to-noise ratio of the IR images was on average 38% higher than that of the corresponding 4D phase.

Conclusions:
4D magnetic resonance imaging is superior in that no trigger delay time needs to be determined and an additional wholeheart cine study can be obtained.


European Journal of Neuroscience, Vol. 26, pp. 190?198, 2007

Mouse model mimics multiple sclerosis in the clinico-radiological paradox

Jens Wuerfel1, Eva Tysiak1, Timour Prozorovski1, Maureen Smyth1, Susanne Mueller2, Jörg Schnorr3, Matthias Taupitz3 and Frauke Zipp1

1Cecilie-Vogt-Clinic for Molecular Neurology, Charite? ? University Medicine Berlin, and Max-Delbrueck-Center for Molecular Medicine, Germany 2Berlin Neuro Image Center, Charite? ? University Medicine Berlin, Germany 3Department of Radiology, Neuroscience Research Center, Charite? ? University Medicine Berlin, Germany E-mail: frauke.zipp[at]charite[dot]de

Abstract:
The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL ? J mice, and applied highfield- strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood?brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.