Catherine Chambon

Superparamagnetic iron oxides as positive MR contrast agents: In vitro and in vivo evidence

The ability of superparamagnetic iron oxides (SPIO) and ultrasmall superparamagnetic iron oxides (USPIO) to act as positive contrast enhancers due to a marked T1 relaxivity was investigated. At low concentrations, an important signal enhancement was observed in vitro, reaching 120% for SPIO and 140% for USPIO in a spin echo 500/22 sequence. The more heavily the sequence was T1-weighted the greater the enhancement. As the concentration increased, the signal dropped. The in vivo study of USPIO in the rat showed that at low doses (14 mumol Fe/kg), the myocardial signal was enhanced by 30%, whereas at high doses (77 mumol Fe/kg), it fell by -50%. These results indicate that in T1-weighted spin echo sequences, the MR signal can be enhanced by low concentrations of superparamagnetic compounds. This effect could be useful in perfusion imaging, and is also important for a better understanding of any possible paradoxical positive enhancement which could occur in perfused organs.

Liver positive enhancement after injection of superparamagnetic nanoparticles: Respective role of circulating and uptaken particles

Superparamagnetic nanoparticles have both high r1 and r2 relaxivities responsible for positive or negative enhancement properties. The aim of this study was to investigate to what extent perfusion (circulating particles) and uptake (clustered particles) mechanisms contribute to liver positive or negative enhancement using two different particles, superparamagnetic iron oxides (ferumoxides, AMI 25) and ultrasmall superparamagnetic iron oxides (ferumoxtran, AMI-227). Uptake kinetics were studied after intravenous injection of 20 micromol Fe/kg ferumoxtran on a washout liver model. Livers of 82 rats were surgically isolated and washed with saline infusion. Imaging was performed ex vivo at 0.5T with T1- and T2-weighted sequences. Enhancement kinetics of the liver were studied in vivo using MRI up to 180 min post injection of 20 micromol Fe/kg ferumoxtran (time response study) or 10, 20, 40 micromol Fe/kg ferumoxtran and 20 micromol Fe/kg ferumoxides (dose response study.) Particle uptake occurred early and resulted in a negative enhancement of the washed livers 15 min after injection of both T1 and T2 sequences. In vivo, a positive enhancement was only seen during the first five min with the lowest dose of ultrasmall superparamagnetic iron oxides and the T1 sequence. Uptake and clustering of the particles induced a negative liver enhancement. During the first minutes after injection, when uptake has not significantly occurred, perfusion imaging of the liver at a dose of 10 micromol Fe/kg results in a positive enhancement with T1-weighted sequences.

Evaluation of intrarenal distribution of ultrasmall superparamagnetic iron oxide particles by magnetic resonance imaging and modification by furosemide and water restriction.

Trillaud H, Degrèze P, Combe C, Palussière J, Chambon C, Grenier N. Evaluation of intrarenal distribution of ultrasmall superparamagnetic iron oxide particles by magnetic resonance imaging and modification by furosemide and water restriction. Invest Radiol 1994;29:540-546. RATIONALE AND OBJECTIVES.The steady-state intrarenal distribution of ultrasmall superparamagnetic iron oxide (USPIO) particles in the cortex, the outer medulla (OM), and the inner medulla (IM) was investigated using magnetic resonance imaging in the normal rabbit kidney and in situations that modify the corticopapillary osmotic gradient. METHODS.Experiments were performed on rabbit kidneys with T2-weighted spin-echo sequence and T2-weighted gradient-recalled-echo sequence. The intravenous dose was 27 μmole/kg of iron in all rabbits. Three groups were studied: normally hydrated rabbits (n=5), after water restriction (n=5) to increase the osmotic gradient, and after furosemide injection (n=5) to decrease the osmotic gradient. The signal intensity (SI) was quantified by region of interest placed on the cortex, the OM and the IM. RESULTS.In normally hydrated rabbits, a maximal decrease of the SI after USPIO was noted in the medulla, without significant difference between the OM and the IM on spin-echo sequences. The decrease of the SI was maximal in the IM on gradient-recalled echo sequences. In dehydrated animals, the maximum SI loss was in the OM. The furosemide-induced transient enhancement of the IM lasted a few minutes. CONCLUSIONS.The observed SI changes due to the distribution of the USPIO between OM and IM were not based on modifications of the osmotic gradient. The authors suggest that these SI changes were mostly dependent on the vascular density.

Pharmacokinetics and tolerance of Gd-DOTA (DOTAREM) in healthy volunteers and in patients with chronic renal failure

The aim of this study was to assess the pharmacokinetics and tolerance of Gd-DOTA (DOTAREM) in non-dialysed patients with chronic renal failure. Eight patients with chronic renal failure (creatinine clearance between 10 and 60 ml/min) and four healthy volunteers were given i.v. Gd-DOTA (0.1 mmol/kg). Blood and urine samples were collected. Gd-DOTA tolerance was also studied (vital signs, biological parameters, adverse reactions). In healthy volunteers, Gd-DOTA was rapidly distributed in the extracellular space and almost totally eliminated in the urine (glomerular filtration, 93.3±4.7% of the dose 24 h post injection). In patients with chronic renal failure, a delayed and almost total urinary elimination observed with a correlation between Gd-DOTA clearance and plasma creatinine clearance (r = 0.964). Tolerance was good with no significant modification of renal function or other parameters. These results confirm previous studies and indicates that DOTAREM can be used safely for patients with chronic renal failure.

Gd-DOTA Loaded into Red Blood Cells, a New Magnetic Resonance Imaging Contrast Agents for Vascular System

Soon after the advent of the diagnostic tool Magnetic Resonance Imaging (MRI), magnetic resonance contrast agents were developed and provided to the radiologists an additional tool that would significantly improve the accuracy of this observation. This led particularly to the introduction of Gadolinium (Gd) chelates for clinical use, which are now considered to be efficient markers of extracellular water.1,2

Intraarticular tolerability and kinetics of gadolinium tetra-azacyclododecane tetraacetic acid

RATIONALE AND OBJECTIVES We assessed the tolerability and the intraarticular kinetics of gadolinium tetra-azacyclododecane tetraacetic acid (Gd-DOTA) using magnetic resonance (MR) imaging. METHODS Twelve of 18 dogs received an intraarticular injection of Gd-DOTA solution. Pathologic examination of all joints was performed with assessment of Gd-DOTA bone absorption. Effects of Gd-DOTA on chondrocyte viability and proliferation in vitro were determined using cultures of rabbit chondrocytes. Four dogs underwent MR imaging of the stifle joint before and after intraarticular injection of 0.8 ml Gd-DOTA at a concentration of 2 mmol/l (300 mOsm/l). Intraarticular kinetics of Gd-DOTA were determined from quantitative measurements using repeated sagittal spin-echo T1-weighted images. RESULTS No microscopic changes of the joints or Gd-DOTA bone absorption were detected. No cytotoxicity for chondrocytes was observed at a concentration of 5 mmol/l, but a decreased cell count was observed at a high concentration (50 mmol/l). The intraarticular Gd-DOTA concentration decreased with time according to a logarithmic curve with an intraarticular half-life of 103-152 min (M = 127 min). CONCLUSION Gd-DOTA is a safe intraarticular contrast agent with a long half-life in the joint cavity.

High-performance liquid chromatographic determination of iobitridol in plasma, urine and bile

Iobitridol is a new non-ionic, low-osmolality contrast medium for urography and angiography. We have developed a method for determining iobitridol in body fluids using high-performance liquid chromatography with ultraviolet detection. The method, which is specific and reproducible, does not require an internal standard. Determinations can be carried out in body fluids against a set of standards in ethanol. The method was validated for the quantification of iobitridol in biological samples obtained during pharmacokinetic studies.

Whole body quantitative autoradiographic study of the biodistribution of iobitridol in rats.

RATIONALE AND OBJECTIVES.Iobitridol is a new nonionic low-osmolality contrast medium. During preclinical development of this agent, it was of interest to verify that it behaves like other urographic and angiographic contrast agents (i.e., as a tracer of extracellular fluid). METHODS.Male and female rats were imaged using a quantitative autoradiographic method after intravenous administration of iodinc-125-Iabeled product at a dose of 300 mg iodine/ kg. RESULTS.The radioactivity was rapidly distributed with substantial uptake in the thyroid, kidneys, and skin after 10 minutes. The central nervous system showed no uptake. The radioactivity was rapidly eliminated (i.e., after 24 and 48 hours, only traces were found) except in the thyroid (because of free radiolabeled iodides present in small quantities in the administered soIution).The considerable renal uptake after administration can be attributed to urinary excretion of the radioactivity (86% of the administered dose after 24 hours). Total elimination was achieved after 48 hours. No sex-related effects were observed. CONCLUSION.The absence of a target organ, the abundant and rapid urinary elimination, and the absence of transfer across the blood-brain barrier suggest that iobitridol is a tracer of extracellular fluid.

Animal Studies of Iodized Oils: Iodine Disposition and Physiological Effects

Iodized oils are widely used throughout the world for the treatment of iodine deficiency and endemic goiter, as extensively related in the litterature1,2,3,4,5.

Superparamagnetic iron oxide-enhanced magnetic resonance imaging of experimental liver tumors after mitomycin C administration.

The influence of mitomycin C chemotherapy on superparamagnetic iron oxide (SPIO) uptake by the liver was studied in rats (n = 70). This commonly used antineoplastic drug induces a decrease in the phagocytic function of the macrophage-phagocytic system (MPS). The plasma clearance of SPIO measured by relaxometry followed a biexponential model. The fast component half-life increased from 2.9 minutes in controls to 4.5 minutes in mitomycin C-treated animals. The slow component half-life increased from 11.3 to 36.7 minutes. Nevertheless, the magnetic resonance imaging (MRI) diagnostic efficacy 2 hours after infusion of the superparamagnetic agent AMI 25 (n = 10) was as satisfactory in the treated group as in the untreated one. These MRI results were consistent with the relaxometric T2* liver measurements, which were identical in both groups.