Soraya Benderbous

CARBOXYMETHYL-DEXTRAN-GADOLINIUM-DTPA AS A BLOOD-POOL CONTRAST AGENT FOR MAGNETIC RESONANCE ANGIOGRAPHY : EXPERIMENTAL STUDY IN RABBITS

RATIONALE AND OBJECTIVES The authors evaluate the efficiency of various doses of a paramagnetic macromolecular contrast agent, a gadolinium (Gd)-DTPA-dextran conjugate, as a blood-pool contrast media, in a transverse three-dimensional time-of-flight (TOF) magnetic resonance (MR) angiography sequence of the abdominal aorta in rabbits. METHODS Imaging experiments were performed on a 1.5-T magnet, using a transverse three-dimensional TOF tilted optimized nonsaturating excitation (TONE) sequence. The macromolecular contrast media used was a carboxymethyl-dextran-Gd-DTPA (CMD-Gd-DTPA). Different concentrations of CMD-Gd-DTPA (0.005, 0.01, 0.03, 0.05 mmol Gd/kg) were evaluated. A comparative study using Gd-DOTA (0.01 and 0.1 mmol/kg) was performed. A visual analysis based on the gain in the visualized length of small arteries (renal arteries), and a quantitative analysis based on the percent contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained. RESULTS A signal-to-noise ratio enhancement of the distal part of the aorta and an improvement in the visualized length of the renal arteries were noted for concentrations of CMD-Gd-DTPA ranging form 0.01 to 0.05 mmol Gd/kg. Venous enhancement was noted for concentrations greater than 0.01 mmol Gd/kg when using CMD-Gd-DTPA or Gd-DOTA. CONCLUSION Carboxymethyl-dextran-Gd-DTPA reduced, in part, the saturation effect in a three-dimensional transverse TOF TONE MR angiography in rabbits. To prevent venous enhancement, observed with the higher concentrations used in this study, a decrease in the polydispersity of the polymer should be a goal in the future. Rapid extravasation of the low-molecular weight fraction of the polymer could explain the venous enhancement.

P760 and P775: MRI contrast agents characterized by new pharmacokinetic properties.

Rationale and objectives: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties.Methods: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging.Results and conclusion: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

A new gadolinium‐based contrast agent for magnetic resonance imaging of brain tumors: Kinetic study on a C6 rat glioma model

T1‐weighted magnetic resonance imaging (MRI) was used to evaluate the potential interest of a new Gd‐based contrast agent, termed P760, to characterize brain tumor heterogeneity and vascularization and to delineate regions containing permeable vessels. The C6 rat glioma model was used as a model of high‐grade glioblastoma. The signal enhancement was measured as a function of time in the vascular compartment and in different regions of interest (ROIs) within the tumor after the injection of 0.02 mmol kg−1 of P760. The results were compared to those obtained after the injection of 0.1 mmol kg−1 of Gd‐DOTA. We showed that P760, in spite of a Gd concentration five times smaller, produces an enhancement in the blood pool similar to that produced by Gd‐DOTA. It was shown that P760 makes possible an excellent delineation of regions containing vessels with a damaged blood‐brain barrier (BBB). Images acquired 5–10 minutes after P760 injection showed the location of permeable vessels more accurately than Gd‐DOTA‐enhanced images. The enhancement produced in the tumor by P760 was, however, less than that produced by Gd‐DOTA. The extravasation and/or diffusion rate of P760 in the interstitial medium were found to be strongly reduced, compared to those found with Gd‐DOTA. This study suggests that the new contrast agent has promising capabilities in clinical imaging of brain tumors. J. Magn. Reson. Imaging 2001;14:97–105.

USPIO-Enhanced MR imaging of glycerol-induced acute renal failure in the rabbit

Enhanced-MR imaging in combination with ultrasmall superparamagnetic iron oxide (USPIO) was used in the glycerol-induced model of acute renal failure (ARF) in the rabbit to detect renal perfusion abnormalities. A control group (n = 5) and an ARF group (n = 5) were studied after intramuscular injection of glycerol (10 ml/kg) with T2-weighted spin-echo sequence at 1.5 T and a 27 mumol/kg IV dose of iron. The signal intensity (SI) was quantified in the cortex, the outer medulla (OM), and the inner medulla (IM). In control rabbits, the maximum SI decrease after USPIO injection was in the OM (76% +/- 3.6), as this is the region of maximal vascular density, then in the IM (73.4% +/- 2.9). In the glycerol group, SI loss in the OM (61% +/- 12.6) and the IM (45.2% +/- 16.24) was significant less than in the control group (p < .05). Pathology results showed fibrinous thrombus in the efferent arterioles and congestive aspect of the vasa recta in the medulla. We argue that a reduced medullary concentration of USPIO in the renal failure group is indicative of medullary hypoperfusion.

Capillary leakage of a macromolecular MRI agent, carboxymethyldextran-Gd-DTPA, in the liver : Pharmacokinetics and imaging implications

Capillary leakage of a macromolecular contrast agent, Carboxymethyl Dextran-Gd-DTPA (CMD-Gd-DTPA) was characterized in a highly permeable system, the liver, to assess its potential as a blood pool marker. Its elimination kinetics in hepatic lymph were compared in nephrectomized rabbits with that of a tracer of extra cellular fluid space, Gd-DOTA. Four parameters were defined: volume of distribution, normalized initial leakage rate (ILRn), maximum ratio of lymph and plasma concentrations (max Cl/Cp), and the time to obtain this maximum ratio. The effect of this leakage was studied on MR images by comparing liver contrast enhancement after injection and after almost total removal of the contrast agent from the blood by exchange transfusion. Capillary leakage of CMD-Gd-DTPA was detected in lymph. Compared to Gd-DOTA, it was slower (ILRn = 0.36 10(-5) l min-1 for CMD-Gd-DTPA and ILRn = 2.6 10(-5) l min-1 for Gd-DOTA), less abundant (max Cl/Cp was 80% for CMD-Gd-DTPA and 100% for Gd-DOTA). Liver enhancement remained stable, which indicated that the leakage did not modify the enhancement induced by the intravascular fraction of the contrast agent. These results obtained in a highly permeable capillary model indicate that this agent can be used as a selective blood pool enhancer.

Reversibility of experimental acute renal failure in rats: Assessment with USPIO-enhanced MR imaging

The purpose of this study was to evaluate the potential reversibility of kidney lesions in an experimental model of acute renal failure using ultra‐small particles of iron oxide (USPIO)‐enhanced magnetic resonance (MR) imaging. This study was conducted in 21 uninephrectomized rats using a model of iodinated contrast media‐induced renal failure. Thirteen rats received selective intraarterial renal administration of diatrizoate (370 mg/ml) and were compared with two control groups, including six animals injected with saline and two noninjected animals.

Equilibrium phase MR angiography of the aortic arch and abdominal vasculature with the blood pool contrast agent CMD-A2-Gd-DOTA in pigs

Meglumine‐carboxymethyldextran‐ethylenediamino‐gadoterate (CMD‐A2‐Gd‐DOTA) was evaluated as a blood pool contrast agent for magnetic resonance angiography (MRA). MRA of large body vasculature was performed in seven pigs using a gradient‐echo sequence at 1.5 T before and after 0.05 mmol/kg CMD‐A2‐Gd‐DOTA injection. The signal‐ and contrast‐to‐noise ratios (SNRs, CNRs) were measured, as well as the pharmacokinetic clearance pattern. CMD‐A2‐Gd‐DOTA visualized the vasculature with a high SNR and CNR for over 110 minutes after injection, but for the renal arteries the CNR was only significant within 15 minutes. Image quality was maximum within 15 minutes, producing enhancement (mean ± SD) as follows: aortic arch 738 ± 272%, abdominal aorta 393 ± 123%, left renal artery 202 ± 95%, right renal artery 248 ± 107%, inferior vena cava 371 ± 129%, and portal vein 513 ± 145%, all P values ≤0.001. The clearance pattern was triphasic. Due to the excellent enhancement of vasculature without background enhancement, CMD‐A2‐Gd‐DOTA is potentially a useful MR blood pool contrast agent for equilibrium phase MRA. J. Magn. Reson. Imaging 1999;9:777–785.

Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool agents for MR angiography.

RATIONALE AND OBJECTIVES To evaluate the use of two new blood pool contrast agents (P760, P775) compared with a low-molecular-weight gadolinium chelate in MR angiography. METHODS The r1 efficiency of P760 was evaluated in vitro at 1.5 T; 3D abdominal contrast-enhanced MR angiography with qualitative analysis was compared in four rabbits after injection of incremental doses of P760 and in one rabbit after Gd-DOTA. A dynamic MR study was performed using a 2D T1-weighted turbo-flash MR sequence after injection of P760, P775, and Gd-DOTA. Each compound was tested at equivalent doses in three rabbits to assess r1 efficiency. Quantitative analysis of signal intensity in the aorta, the inferior vena cava, the renal cortex, and the medulla was performed. RESULTS In vitro, the r1 efficiency of P760 was 23.3 mmol(-1) x L x sec(-1) at 1.5 T. Injection of a dose of P760 10 times less than Gd-DOTA allowed similar vessel visualization. The signal intensity peak and first-pass contrast kinetics in the aorta and the inferior vena cava were similar with the three products. Compared with P760 and Gd-DOTA, P775 allowed a greater renal cortex signal intensity at the first pass and a faster decrease on delayed images. CONCLUSIONS The superior r1 efficiency of P760 and P775 was confirmed in vitro and in vivo at 1.5 T compared with Gd-DOTA, and P775 proved to be a rapid-clearance blood pool agent.

Experimental investigation of the delivery pathway of ultrasmall superparamagnetic iron oxide to lymph nodes

F rom the few studies of the uptake mechanisms of ultmsmall superparamagnetic iron oxide (USPIO) dextran-coated part!cles by the lymph nodes [1-5], it appears that the conclusions are still controversial. Two mechanisms are the subject of speculation: (1) opsonization of the particles, which could favor a direct intranodal delivery mechanism by the blood, and (2) interstitial extravasation, which could favor lymph drainage. To improve understanding of the relative importance of these two mechanisms, the following study was undertaken using a model of isolated node in the rabbit, which is known to be nonimmunosensitive to dextran.