First clinical trial of a new superparamagnetic iron oxide for use as an oral gastrointestinal contrast agent in MR imaging

The authors report the results of preclinical testing and initial clinical application of a superparamagnetic iron oxide specifically prepared as a contrast agent for magnetic resonance (MR) imaging of the gastrointestinal tract. MR imaging was performed at 0.6 and 1.5 T in 15 volunteers. Images of the upper abdomen and pelvis were obtained before and after ingestion of the contrast material at doses of 22.5-225.0 mg of iron in 600-900 L. Two readers scored the images. Delivery of contrast material into the proximal and distal small bowel, with obvious loss of signal intensity (T2 enhancement), was achieved in all subjects. Enhanced images showed improved delineation of the head and tail of the pancreas, anterior margins of the kidneys, and paraaortic region. The contrast agent did not generate artifacts, an improvement over prototype formulations evaluated previously in animals. Except for a brief episode of diarrhea in five subjects, the agent was well tolerated. Use of this contrast agent improved the diagnostic quality of abdominal MR images by enabling the distinction of the bowel from nonbowel structures at concentrations that did not produce image distortion.     

OMR, a positive bowel contrast agent for abdominal and pelvic MR imaging: safety and imaging characteristics.

To determine the safety and imaging characteristics of OMR--an effervescent solution of ferric ammonium citrate--as a bowel contrast agent, magnetic resonance (MR) imaging at 1.5 T was performed in 29 volunteers. T1- and T2-weighted images of the upper abdomen and pelvis were obtained before and after oral administration of OMR at doses of 100-400 mg of iron in 300-600 mL of water. Respiratory-ordered phase encoding and presaturation pulses were used routinely for artifact suppression. All dose levels of OMR provided marking of the bowel by increasing intraluminal signal intensity; however, the degree and percentage of small bowel opacification appeared more prominent at higher dose levels of iron. Semisolid or watery bowel movements were noted in 31% of subjects, but no clinically important laboratory abnormalities were seen. OMR improved delineation of the head of the pancreas on T1-weighted images in 72% of subjects but was less useful in defining the body and tail. OMR is a safe and effective bowel contrast agent for MR imaging. Because artifacts due to movement of hyperintense bowel may degrade the images, OMR may be most useful on short TR/TE or fast imaging pulse sequences or when combined with antiperistaltic agents.     

Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging

Superparamagnetic iron oxide MR imaging contrast agents have been the subjects of extensive research over the past decade. The iron oxide particle size of these contrast agents varies widely, and influences their physicochemical and pharmacokinetic properties, and thus clinical application. Superparamagnetic agents enhance both T1 and T2/T2* relaxation. In most situations it is their significant capacity to reduce the T2/T2* relaxation time to be utilized. The T1 relaxivity can be improved (and the T2/T2* effect can be reduced) using small particles and T1-weighted imaging sequences. Large iron oxide particles are used for bowel contrast [AMI-121 (i.e. Lumirem and Gastromark) and OMP (i.e. Abdoscan), mean diameter no less than 300 nm] and liver/spleen imaging [AMI-25 (i.e. Endorem and Feridex IV, diameter 80-150 nm); SHU 555A (i.e. Resovist, mean diameter 60 nm)]. Smaller iron oxide particles are selected for lymph node imaging [AMI-227 (i.e. Sinerem and Combidex, diameter 20-40 nm)], bone marrow imaging (AMI-227), perfusion imaging [NC100150 (i.e. Clariscan, mean diameter 20 nm)] and MR angiography (NC100150). Even smaller monocrystalline iron oxide nanoparticles are under research for receptor-directed MR imaging and magnetically labeled cell probe MR imaging. Iron oxide particles for bowel contrast are coated with insoluble material, and all iron oxide particles for intravenous injection are biodegradable. Superparamagnetic agents open up an important field for research in MR imaging.     

Magnetite albumin suspension: a superparamagnetic oral MR contrast agent

Suspensions of magnetite albumin microspheres (MAM), a new biodegradable particulate iron superparamagnetic MR contrast material, were evaluated in vitro and in vivo as an oral contrast agent. MAM is stable over a broad range of pH and tolerates proteolytic enzyme exposure over 24 hr in vitro. MAM possesses a much larger magnetic moment than do paramagnetic contrast agents. The transverse relaxation rate (R2) of MAM can be as much as 40 times the longitudinal relaxation rate (R1). In vitro spectroscopy studies confirm the potency of MAM in promoting T2 relaxation at concentrations of 10-1000 mg/l. Preliminary studies in rabbits and dogs show that in contrast to oral gadolinium-DTPA, which causes increased signal in bowel, MAM causes marked signal loss in the stomach and small bowel on both T1- and T2-weighted pulse sequences. Radionuclide labeling studies of MAM suspension with 99mTc show no evidence of absorption of MAM suspension from the gastrointestinal tract in small animals. Superparamagnetic suspensions such as MAM that reduce bowel signal on T1- and T2-weighted pulse sequences offer the unique benefit of reducing motion artifacts throughout the gastrointestinal tract, which should allow for improved evaluation of intra- and retroperitoneal diseases, particularly with high-field strength and gradient-echo "fast-scan techniques." Unlike paramagnetic material, MAM appears effective as a small-bowel contrast material.     

Intraluminal contrast enhancement and MR visualization of the bowel wall: efficacy of PFOB.

Efforts to develop satisfactory intraluminal gastrointestinal contrast agents for magnetic resonance (MR) imaging have focused on depicting only the bowel lumen to exclude possible involvement by a pathologic process. To determine whether the bowel wall can be adequately imaged with use of the contrast agent and whether bowel wall visualization is a better index of the utility of the contrast agent for MR imaging, perfluoroocytlbromide (PFOB) was studied in human subjects. Twenty consecutive patients referred for abdominal or pelvic MR imaging were selected. All patients were given 400-1,000 mL of PFOB orally. MR imaging was performed at 0.38 and 1.5 T with T1- and T2-weighted spin-echo pulse sequences before and after administration of PFOB. The images were graded independently by three blinded readers. All readers reported significantly superior conspicuity of the bowel lumen and wall after PFOB than before PFOB administration (P less than .002). Among the post-PFOB studies, those with superior bowel wall visualization demonstrated superior overall image quality. In three patients, lesions were optimally demonstrated because the relationship of the process to the bowel wall, rather than just to the lumen, was identified. In two patients, masses arising within the bowel wall could be identified prospectively only when the bowel wall was adequately imaged. The authors conclude that while lumen identification is improved with PFOB, its greatest clinical utility may be in facilitating intestinal wall visualization.     

Iron oxide-enhanced MR lymphography: initial experience

The detection of nodal metastases is of utmost importance in oncologic imaging. Ultrasmall superparamagnetic iron oxide particles (USPIO) are novel contrast agents specifically developed for MR lymphography. After intravenous administration, they are taken up by the macrophages of the lymph nodes, where they accumulate. They reduce the signal intensity (SI) of normally functioning nodes on postcontrast T2-and T2*-weighted images through the magnetic susceptibility effects on iron oxide. Metastatic nodes, in which macrophages are replaced by tumor cells, show no significant change in SI on postcontrast T2-and T2*-weighted images. Early clinical experience suggests that USPIO-enhanced MR lymphography improves the sensitivity and specificity for the detection of nodal metastases. It also suggests that micrometastases could be detected in normal-sized nodes. This article reviews the physiochemical properties of USPIO contrast agents, their enhancement patterns, and early clinical experience.     

Perfluoroctylbromide as a gastrointestinal contrast agent for MR imaging: use with and without glucagon

The utility of perfluoroctylbromide (PFOB) as a gastrointestinal contrast agent for magnetic resonance (MR) imaging was evaluated with MR examinations performed in 30 subjects (16 healthy volunteers and 14 patients). Transaxial T1-, proton density-, and T2-weighted MR images were acquired in each subject before and after the administration of PFOB. The healthy volunteers each underwent two sets of post-PFOB MR examinations, one before and one after glucagon administration. The degree of bowel marking, clarity of bowel-wall visualization, ability to distinguish bowel from adjacent parenchymal organs, and severity of phase-encoding artifacts were independently analyzed by two reviewers. Oral administration of PFOB significantly (P less than .001) increased the percentage of bowel loops with low signal intensity. Subcutaneous administration of glucagon significantly (P less than .001) increased the clarity of bowel-wall visualization on post-PFOB MR studies. The severity of phase-encoding artifacts did not change substantially after administration of PFOB or glucagon.     

Evaluation of potential gastrointestinal contrast agents for echoplanar MR imaging

Although the diagnostic application of echoplanar imaging (EPI) has until now been limited, recent technical advances provide anatomic resolution and signal-to-noise ratios comparable to that of conventional MR imaging. The purpose of this study was to investigate approved aqueous gastrointestinal contrast agents for use in abdominal EPI. Conventional and echoplanar MR imaging experiments were performed with 1.0 Tesla whole body systems. Phantom measurements of Gastrografin, barium sulfate suspension, oral gadopentetate dimeglumine, water, and saline were performed. Signal intensity (SI) of aqueous oral barium sulfate and iodine based CT contrast agents was lower on conventional spin-echo (SE), Flash, and Turbo-Flash images than on EP images. The contrast agents exhibited higher SI on T2-weighted SE PE images and TI-time dependence on inversion recovery EP-images. The barium sulfate suspension was administered in volunteers to obtain information about bowel lumen enhancement and susceptibility artifacts. Oral administration of the aqueous barium sulfate suspension increased bowel lumen signal and reduced susceptibility artifacts. Approved aqueous gastrointestinal contrast media or flavored saline with long relaxation times may serve as safe, simple, and effective gastrointestinal contrast agents in abdominal EPI. Correspondence to: P. Reimer     

Dynamic signal intensity changes in liver with superparamagnetic MR contrast agents.

The dynamic effects of three different superparamagnetic magnetic resonance (MR) contrast agents on liver signal were evaluated with an echo-planar imaging technique. The contrast agents were (a) USPIO (ultrasmall superparamagnetic iron oxide), which has a long blood half-life and was developed for MR imaging of lymph nodes and bone marrow; (b) AG (arabinogalactan)-USPIO, an asialoglycoprotein receptor--directed iron oxide with hepatocyte uptake; and (c) AMI-25, a conventional reticuloendothelial iron oxide agent. Dynamic liver signal intensity (SI) curves reflect different uptake mechanisms for the different agents. Receptor blocking experiments indicate that intracellular redistribution or clustering of the AG-USPIO (known to occur from electron microscopy studies) does not contribute to the decrease in liver SI. Monitoring liver SI over time with echo-planar imaging may provide a better understanding of the kinetics of the growing number of MR contrast agents and allow optimization of imaging protocols to exploit peak enhancement.     

Differentiation of hepatocellular carcinomas from hyperplastic nodules induced in rat liver with ferrite-enhanced MR imaging.

The potential of superparamagnetic ferrite particles in magnetic resonance (MR) imaging to help differentiate between hyperplastic nodular lesions in the liver and hepatocellular carcinomas was evaluated with chemically induced liver tumors in cirrhotic rats. Ferrite particles decreased the signal intensity of hyperplastic nodules but not that of hepatocellular carcinomas, and stainable iron was found in the former but not in the latter with Prussian blue iron stain. T1-weighted spin-echo images made little contribution to the differentiation between these two lesions, while T2-weighted spin-echo images were effective for this purpose, since ferrite particles cause T2 shortening. Ferrite-enhanced MR imaging may be useful in differentiating these two lesion types according to their signal intensity changes on images, because Kupffer cells are present in hyperplastic nodular lesions but rarely in hepatocellular carcinomas.     

Formulation of radiographically detectable gastrointestinal contrast agents for magnetic resonance imaging: effects of a barium sulfate additive on MR contrast agent effectiveness.

Complete and homogeneous distribution of gastrointestinal (GI) contrast media are important factors for their effective use in computed tomography as well as in magnetic resonance (MR) imaging. A radiographic method (using fluoroscopy or spot films) could be effective for monitoring intestinal filling with GI contrast agents for MR imaging (GICMR), but it would require the addition of a radiopaque agent to most GICMR. This study was conducted to determine the minimum amount of barium additive necessary to be radiographically visible and to evaluate whether this additive influences the signal characteristics of the GICMR. A variety of barium sulfate preparations (3-12% wt/vol) were tested in dogs to determine the minimum quantity needed to make the administered agent visible during fluoroscopy and on abdominal radiographs. Solutions of 10 different potential GI contrast agents (Gd-DTPA, ferric ammonium citrate, Mn-DPDP, chromium-EDTA, gadolinium-oxalate, ferrite particles, water, mineral oil, lipid emulsion, and methylcellulose) were prepared without ("nondoped") and with ("doped") the barium sulfate additive. MR images of the solutions in tubes were obtained at 0.38 T using 10 different spin-echo pulse sequences. Region of interest (ROI) measurements of contrast agent signal intensity (SI) were made. In addition, for the paramagnetic contrast media, the longitudinal and transverse relaxivity (R1 and R2) were measured. A 6% wt/vol suspension of barium was the smallest concentration yielding adequate radiopacity in the GI tract. Except for gadolinium-oxalate, there was no statistically significant difference in SI for doped and non-doped solutions with most pulse sequences used. In addition, the doped and nondoped solutions yielded R1 and R2 values which were comparable. We conclude that barium sulfate 6% wt/vol added to MR contrast agents produces a suspension with sufficient radiodensity to be viewed radiographically, and it does not cause significant alteration in the MR signal appearance of most GICMR. These formulations can be useful for achieving optimal filling of the gastrointestinal tract prior to MRI.     

Targeting of hematopoietic progenitor cells with MR contrast agents

PURPOSE: To label human hematopoietic progenitor cells with various magnetic resonance (MR) imaging contrast agents and to obtain 1.5-T MR images of them. MATERIALS AND METHODS: Hematopoietic progenitor cells, labeled with ferumoxides, ferumoxtran, magnetic polysaccharide nanoparticles-transferrin, P7228 liposomes, and gadopentetate dimeglumine liposomes underwent MR imaging with T1- and T2-weighted spin-echo and fast field-echo sequences. Data were analyzed by measuring MR signal intensities and R1 and R2* relaxation rates of labeled cells and nonlabeled control cells. Mean quantitative data for the various contrast agent groups were assessed for significant differences compared with control cells by means of the Scheffe test. As a standard of reference, MR imaging data were compared with electron microscopic and spectrometric data. RESULTS: For all contrast agents, intracellular cytoplasm uptake was demonstrated with electron microscopy and was quantified with spectrometry. When compared with nonlabeled control cells, progenitor cells labeled with iron oxides showed significantly (P <.05) increased R2*. Cells labeled with gadopentetate dimeglumine liposomes showed significantly increased R1. Detection thresholds were 5 x 10(5) cells for gadopentetate dimeglumine liposomes and ferumoxtran, 2.5 x 10(5) cells for ferumoxides and P7228 liposomes, and 1 x 10(5) cells for magnetic polysaccharide nanoparticles-transferrin. CONCLUSION: Hematopoietic progenitor cells can be labeled with MR contrast agents and can be depicted with a standard 1.5-T MR imager.     

Intraluminal contrast agents for MR imaging of the abdomen and pelvis

Magnetic resonance (MR) imaging of the abdomen and pelvis with use of gastrointestinal (GI) contrast agents is slowly emerging as a valuable diagnostic tool. In the past few years, considerable effort has been expended on developing an oral contrast agent to serve as a bowel marker during abdominal and pelvic imaging. Four major categories of agents have been studied: compounds with positive contrast-enhancing characteristics (ie, which increase signal intensity), which may be either miscible or immiscible with bowel contents, and compounds with negative contrast-enhancing characteristics (ie, which decrease signal intensity), which also may be miscible or immiscible. Compared with precontrast images, MR images acquired after administration of GI contrast agents have shown increased anatomic delineation of the bowel lumen, pancreas, and paraaortic nodes, allowing increased detection of pancreatic lesions, improved assessment of bowel wall lesions, and distinction between intrahepatic and extrahepatic lesions. This review focuses on the general physics and requirements for intraluminal GI contrast media for MR imaging, the currently used intraluminal agents and their regulatory status, current and near-future availability, and cost considerations.     

Optimization of oral contrast agents for MR imaging of the small bowel

Effect on small-bowel distention of additives to water as contrast agents for magnetic resonance (MR) imaging was assessed. Oral contrast agents included water and water in combination with mannitol, a bulk fiber laxative, locust bean gum, and a combination of mannitol and locust bean gum. Filling of the small bowel was quantified on coronal images obtained with two-dimensional true fast imaging with steady-state precession sequence; bowel diameters were measured. Ingestion of water with locust bean gum and mannitol provided the best distention of the small bowel. MR imaging of the small bowel with oral administration of water can be improved with addition of osmotic and nonosmotic substances that lead to decreased water resorption.     

Congenital anomalies of the small intestine, colon, and rectum.

Congenital anomalies of the gastrointestinal tract are a significant cause of morbidity in children and, less frequently, in adults. These abnormalities include developmental obstructive defects of the small intestine, anomalies of the colon, anomalies of rotation and fixation, anorectal anomalies, and intestinal duplications. Neonates with complete high intestinal obstruction do not usually require further radiologic evaluation following radiography, whereas those with complete low obstruction should undergo a contrast material enema examination. An upper gastrointestinal series must be performed in all patients with incomplete intestinal obstruction because management is different in each case. In low intestinal obstruction, ultrasonography (US) may help differentiate between small bowel obstruction and colonic obstruction. In addition, US can help correctly identify meconium ileus and meconium peritonitis and is useful in the diagnosis of enteric duplication cysts. In malrotation and anorectal anomalies, computed tomography (CT) and magnetic resonance (MR) imaging can provide superb anatomic detail and added diagnostic specificity. Intestinal duplications manifest as an abdominal mass at radiography, contrast enema examination, or US. At CT, most duplications manifest as smoothly rounded, fluid-filled cysts or tubular structures with thin, slightly enhancing walls. At MR imaging, the intracystic fluid has heterogeneous signal intensity on T1-weighted images and homogeneous high signal intensity on T2-weighted images. Familiarity with these gastrointestinal abnormalities is essential for correct diagnosis and appropriate management.     

Cine magnetic resonance imaging of the small bowel: comparison of different oral contrast media

PURPOSE: To evaluate several substances regarding small bowel distension and contrast on balanced steady-state free precession (bSSFP) cine magnetic resonance (MR) images. MATERIAL AND METHODS: Luminal contrast was evaluated in 24 volunteers after oral application of two different contrast agent groups leading to either bright lumen (pineapple, blueberry juice) or dark lumen (tap water, orange juice) on T1-weighted images. Bowel distension was evaluated in 30 patients ingesting either methylcellulose or mannitol solution for limiting intestinal absorption. Fifteen patients with duodeno-jejunal intubation served as the control. Quantitative evaluation included measurement of luminal signal intensities and diameters of four bowel segments, qualitative evaluation assessed luminal contrast and distension on a five-point scale. RESULTS: Quantitative and qualitative evaluation of the four contrast agents revealed no significant differences regarding luminal contrast on bSSFP images. Quantitative evaluation revealed significantly lower (P<0.05) small bowel distension for three out of four segments (qualitative evaluation: two out of four segments) for methylcellulose in comparison to the control. Mannitol was found to be equal to the control. CONCLUSION: Oral ingestion of tap water or orange juice in combination with mannitol is recommended for cine MR imaging of the small bowel regarding luminal contrast and small bowel distension on bSSFP sequences.     

Blueberry juice used per os in upper abdominal MR imaging: composition and initial clinical data

The aim of this study was to evaluate the use of a commercially available blueberry juice (BJ) both as a positive and negative oral contrast agent and to present the exact contents of paramagnetic ions. The concentration of Mn and Fe were determined in tinned myrtilles in syrup (atomic absorption). Nine healthy volunteers and 12 patients (age range 20–65 years) were examined using a 1-T MR scanner before and after per os administration of 430 ml of BJ. A qualitative analysis of signal alterations in the stomach, duodenum, and proximal small intestine was performed. In addition, a quantitative analysis was assessed in terms of signal-to-noise ratio calculation. The mean concentration ( ×± SD) of the ions found in the content of the three cans were 3.3 ± 0.4 μg/g for iron and 20.6 ± 2.6 μg/g for manganese. Based on the qualitative evaluation, signal alteration on T1-weighted images after administration of BJ was statistically significant in the stomach and duodenum, but not in the proximal small bowel. Signal alteration on T2-weighted images was not statistically significant in any part of the gastrointestinal tract. The quantitative analysis of the T1- and T2 shortening showed that BJ is efficient with only T1-weighted sequences, and this applied to the stomach, duodenum, and proximal small bowel. Blueberry juice can be used as an oral contrast agent in upper abdominal MR for T1-weighted imaging. Received: 7 September 1999; Revised: 29 November 1999; Accepted: 16 February 2000     

Gadopentetate dimeglumine as a bowel contrast agent: safety and efficacy

To determine the safety and efficacy of gadopentetate dimeglumine as a bowel contrast agent, magnetic resonance (MR) imaging (0.5 T) was performed with a formulation of gadopentetate dimeglumine (1.0 mmol/L of gadopentetate dimeglumine, 15 g/L of mannitol, 6-17 mL/kg) in 133 patients with intraabdominal mass lesions. Mostly short-lived gastrointestinal side effects were noted in 32% of patients. Gadopentetate dimeglumine provided uniform hyperintense marking of the bowel and contrast enhancement in the region of interest in 81% of patients. Among 78 patients with images obtained both before and after administration of contrast material, post-contrast improvement of lesion delineation was found in 62%. Among 55 patients with only postcontrast images, gadopentetate dimeglumine proved useful in 65%. Intravenous injection of scopolamine or glucagon effectively eliminated "ghost" images of the opacified bowel in 105 of 109 cases. The authors conclude that gadopentetate dimeglumine is a safe and effective bowel contrast agent for MR imaging.     

Contrast agents for MR imaging of the liver

A variety of different categories of contrast agents, and within each category a number of individual agents, are currently available for clinical use in magnetic resonance (MR) imaging of the liver. In this review, the use of nonspecific extracellular gadolinium chelates, reticuloendothelial system-specific iron oxide particulate agents, hepatocyte-selective agents, and combined perfusion and hepatocyte-selective agents are described. Most clinical experience is with nonspecific extracellular gadolinium chelates. The relatively low cost, safety, good patient tolerance, and ability to help detect and characterize a wide range of liver diseases have rendered gadolinium chelates as commonly used agents. Reticuloendothelial system-specific agents improve lesion detection by decreasing the signal intensity of background liver on T2-weighted MR images, which increases the conspicuity of focal hepatic lesions with negligible reticuloendothelial cells (eg, metastases). Hepatocyte-selective agents increase the signal intensity of background liver on T1-weighted images, which increases the conspicuity of focal lesions that do not contain hepatocytes (eg, metastases). The clinical application of the different categories of contrast agents, techniques for their administration, sequences to be used, and appearances of common entities on contrast agent-enhanced studies are described.