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Background: Previous in vitro studies have described sub-linear longitudinal and heightened transverse H 2 O relaxivities of gadolinium-based contrast agents (GBCAs) in blood due to their extracellular nature. However, in vivo validation is lacking., Purpose: Validate theory describing blood behavior of R 1 and R 2 * in an animal model., Study Type: Prospective, animal., Animal Model: Seven swine (54-65 kg)., Field Strength/sequence: 1.5 T; time-resolved 3D spoiled gradient-recalled echo (SPGR) and quantitative Look-Locker and multi-echo fast field echo sequences., Assessment: Seven swine were each injected three times with 0.1 mmol/kg intravenous doses of one of three GBCAs: gadoteridol, gadobutrol, and gadobenate dimeglumine. Injections were randomized for rate (1, 2, and 3 mL/s) and order, during which time-resolved aortic 3D SPGR imaging was performed concurrently with aortic blood sampling via an indwelling catheter. Time-varying [GBCA] was measured by mass spectrometry of sampled blood. Predicted signal intensity (SI) was determined from a model incorporating sub-linear R 1 and R 2 * effects (whole-blood model) and simpler models incorporating linear R 1 , with and without R 2 * effects. Predicted SIs were compared to measured aortic SI., Statistical Tests: Linear correlation (coefficient of determination, R 2 ) and mean errors were compared across the SI prediction models., Results: There was an excellent correlation between predicted and measured SI across all injections and swine when accounting for the non-linear dependence of R 1 and high blood R 2 * (regression slopes 0.91-1.04, R 2  ≥ 0.91). Simplified models (linear R 1 with and without R 2 * effects) showed poorer correlation (slopes 0.67-0.85 and 0.54-0.64 respectively, both R 2  ≥ 0.89) and higher averaged mean absolute and mean square errors (128.4 and 177.4 vs. 42.0, respectively, and 5506 and 11,419 vs. 699, respectively)., Data Conclusion: Incorporating sub-linear R 1 and high first-pass R 2 * effects in arterial blood models allows accurate SPGR SI prediction in an in vivo animal model, and might be utilized when modeling MR blood SI., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 1., (© 2023 International Society for Magnetic Resonance in Medicine.)

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings ( p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin ( p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Background: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe., Methods: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting., Results: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious., Conclusions: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Purpose: The aim of this study was to investigate the presence and chemical forms of residual gadolinium (Gd) in rat brain after a single dose of Gd-based contrast agent., Methods: Four groups of healthy rats (2 sacrifice time-points, n = 10/group, 80 rats in total) were randomized to receive a single intravenous injection of 1 of the 3 Gd-based contrast agents (GBCAs) (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) or the same volume of 0.9% saline solution. The injected concentration was 0.6 mmol/kg, corresponding to a concentration of 0.1 mmol/kg in humans after body surface normalization between rats and humans (according to the US Food and Drug Administration recommendations). Animals were sacrificed at 2 washout times: 1 (M1) and 5 (M5) months after the injection. Total Gd concentrations were determined in cerebellum by inductively coupled plasma mass spectrometry. Gadolinium speciation was analyzed by size-exclusion chromatography coupled to inductively coupled plasma mass spectrometry after extraction from cerebellum., Results: A single injection of a clinically relevant dose of GBCA resulted in the detectable presence of Gd in the cerebellum 1 and 5 months after injection. The cerebellar total Gd concentrations after administration of the least stable GBCA (gadodiamide) were significantly higher at both time-points (M1: 0.280 ± 0.060 nmol/g; M5: 0.193 ± 0.023 nmol/g) than those observed for macrocyclic gadoterate (M1: 0.019 ± 0.004 nmol/g, M5: 0.004 ± 0.002 nmol/g; P < 0.0001). Gadolinium concentrations after injection of gadobenate were significantly lower at both time-points (M1: 0.093 ± 0.020 nmol/g; M5: 0.067 ± 0.013 nmol/g; P < 0.05) than the Gd concentration measured after injection of gadodiamide. At the 5-month time-point, the Gd concentration in the gadoterate group was also significantly lower than the Gd concentration in the gadobenate group (P < 0.05). Gadolinium speciation analysis of the water-soluble fraction showed that, after injection of the macrocyclic gadoterate, Gd was still detected only in its intact, chelated form 5 months after injection. In contrast, after a single dose of linear GBCAs (gadobenate and gadodiamide), 2 different forms were detected: intact GBCA and Gd bound to soluble macromolecules (above 80 kDa). Elimination of the intact GBCA form was also observed between the first and fifth month, whereas the amount of Gd present in the macromolecular fraction remained constant 5 months after injection., Conclusions: A single injection of a clinically relevant dose of GBCA is sufficient to investigate long-term Gd retention in the cerebellar parenchyma. Administration of linear GBCAs (gadodiamide and gadobenate) resulted in higher residual Gd concentrations than administration of the macrocyclic gadoterate. Speciation analysis of the water-soluble fraction of cerebellum confirmed washout of intact GBCA over time. The quantity of Gd bound to macromolecules, observed only with linear GBCAs, remained constant 5 months after injection and is likely to represent a permanent deposition.

Objectives: Being administered intravenously, the tissue that gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging mostly encounter is blood. Herein, it has been investigated how much Gd is internalized by cellular blood components upon the in vitro incubation of GBCAs in human blood or upon intravenous administration of GBCAs to healthy mice. We report results that show how the superb sensitivity of inductively coupled plasma-mass spectrometry (ICP-MS) allows the detection of very tiny amounts of GBCAs entering red blood cells (RBCs) and white blood cells (WBCs). This finding may introduce new insights in the complex matter relative to excretion and retention pathway of administered GBCAs., Materials and Methods: The study was tackled by 2 independent approaches. First, human blood was incubated in vitro with 5 mM of GBCAs (gadoteridol, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine) for variable times (30 minutes, 1 hour, 2 hours, and 3 hours) at 37°C. Then, blood cell components were isolated by using the Ficoll Histopaque method, washed 3 times, mineralized, and analyzed by ICP-MS for total Gd quantification. Furthermore, blood components derived from human blood incubated with gadodiamide or gadoteridol underwent UPLC-MS (ultra performance liquid chromatography-mass spectrometry) analysis for determination of the amount of intact Gd-DTPA-BMA and Gd-HPDO3A. Second, the distribution of Gd in the blood components of healthy CD-1 mice was administered intravenously with a single dose (1.2 mmol/kg) of gadodiamide or gadoteridol. Blood samples were separated and processed at different time points (24 hours, 48 hours, 96 hours, and 10 days after GBCA administration). As for human blood, ICP-MS quantification of total Gd and UPLC-MS determination of the amount of intact GBCAs were carried out., Results: The amount of Gd taken up by RBCs and WBCs was well detectable by ICP-MS. The GBCAs seem to be able to cross the membrane by diffusion (RBCs) or, possibly, by macropinocytosis (WBCs). Ex vivo studies allowed it to be established that the structure of the different GBCAs were not relevant to determine the amount of Gd internalized in the cells. Although the amount of Gd steadily decreases over time in gadoteridol-labeled cells, in the case of gadodiamide, the amount of Gd in the cells does not decrease (even 10 days after the administration of the GBCA). Moreover, while gadoteridol maintains its structural integrity upon cellular uptake, in the case of gadodiamide, the amount of intact complex markedly decreases over time., Conclusions: The detection of significant amounts of Gd in RBCs and WBCs indicates that GBCAs can cross blood cell membranes. This finding may play a role in our understanding of the processes that are at the basis of Gd retention in the tissues of patients who have received the administration of GBCAs.

Background Detection of cerebral lesions at MRI may benefit from a chemically stable and more sensitively detected gadolinium-based contrast agent (GBCA). Gadopiclenol, a macrocyclic GBCA with at least twofold higher relaxivity, is currently undergoing clinical trials in humans. Purpose To determine the relationship between MRI contrast enhancement and the injected dose of gadopiclenol in a glioma rat model compared with those of conventional GBCA at label dose. Materials and Methods Between April and July 2012, 32 rats implanted with C6 glioma received two intravenous injections at a 24-hour interval. The injections were randomly selected among five doses of gadopiclenol (0.025, 0.05, 0.075, 0.1, and 0.2 mmol/kg) and three reference GBCAs (gadoterate meglumine, gadobutrol, and gadobenate dimeglumine) at 0.1 mmol/kg. MRI tumor enhancement was assessed on T1-weighted images before and up to 30 minutes after injection. Two blinded radiologists visually and qualitatively scored contrast enhancement, border delineation, and visualization of tumor morphology. Quantitatively, variations in contrast-to-noise ratio (ΔCNR) between tumor and contralateral parenchyma were calculated at each time point and were compared for each treatment at 5 minutes by using a mixed model after normality test. Results A total of 24 rats underwent the complete protocol ( n = 5-7 per group). A linear dose-dependent ΔCNR relationship was observed between 0.025 and 0.1 mmol/kg for gadopiclenol ( R  2 = 0.99). No difference in ΔCNR was observed between the three reference GBCAs ( P ≥ .55). Gadopiclenol resulted in twofold higher ΔCNR at 0.1 mmol/kg ( P < .001 vs gadobutrol and gadoterate, P = .002 vs gadobenate) and similar ΔCNR at 0.05 mmol/kg ( P = .56, P > .99, and P = .44 compared with gadobutrol, gadobenate, and gadoterate, respectively). For both readers, 0.05 mmol/kg of gadopiclenol improved contrast enhancement, border delineation, and visualization of tumor morphology (scores > 3 compared with scores between 2 and 3 for the marketed GBCA). Conclusion Gadopiclenol at 0.05 mmol/kg yielded comparable change in contrast-to-noise ratio and morphologic characterization of brain tumors compared with gadobenate, gadoterate, or gadobutrol at 0.1 mmol/kg. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Objective: Recent studies reported a signal intensity increase in the deep cerebellar nuclei (DCN) on magnetic resonance images caused by gadolinium deposition after the injection of gadolinium-based contrast agents (GBCAs). There is an ongoing debate if the propensity of a GBCA to deposit gadolinium is primarily determined by its class as either linear or macrocyclic. In the current study, we aimed to compare the amount and the distribution of retained gadolinium of linear and macrocyclic GBCAs in the DCN after a single injection at a dose comparable to a human patient's in a large animal model., Materials and Methods: Eighteen sheep were randomly assigned in 6 groups of 3 animals, which received a single injection of 0.1 mmol/kg body weight of either the macrocyclic GBCAs gadobutrol, gadoteridol, or gadoterate meglumine; the linear GBCAs gadobenate dimeglumine or gadodiamide; or saline. Animals were euthanized 10 weeks after injection. Local distribution and concentration of gadolinium and colocalization to other metals (iron, zinc, copper) in the DCN was assessed by laser ablation-inductively coupled plasma-mass spectrometry., Results: Average gadolinium concentration for the macrocyclic GBCAs and the saline group was below the limit of quantification (5.7 ng/g tissue). In contrast, 14 (for gadobenate) and 27 (for gadodiamide) times more gadolinium than the limit of quantification was found for the linear GBCAs gadobenate (mean, 83 ng/g) or gadodiamide (mean, 155 ng/g brain tissue). Gadolinium distribution colocalized with other metals for linear GBCAs and a specific accumulation in the DCN was found., Discussion: The current study supports the hypothesis that the amount of gadolinium deposited in the brain is primarily determined by its class as either macrocyclic or linear. The accumulation of gadolinium in the DCN for linear GBCAs explains the hyperintensities in the DCN found in previous patient studies with linear GBCAs.

Objectives: The purpose of this study is to determine the frequency and severity of acute allergic-like reactions to gadolinium-based contrast media (GBCM) in children before, during, and after the transition from gadopentetate dimeglumine to gadoterate meglumine as our primary clinical GBCM., Materials and Methods: Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective investigation. Allergic-like reactions to GBCM in pediatric patients were retrospectively assessed from January 2009 to January 2017, which included a departmental change of GBCM from gadopentetate dimeglumine to gadoterate meglumine. Allergic-like reactions were identified from departmental and hospital databases. The number of doses of GBCM was obtained from billing data. Allergic-like reaction frequencies for each GBCM were calculated and compared using the chi-squared test., Results: A total of 32,365 administrations of GBCM occurred during the study period (327 for gadofosveset trisodium; 672 for gadoxetate disodium; 12,012 for gadoterate meglumine; and 19,354 for gadopentetate dimeglumine). Allergic-like reactions occurred after 21 (0.06%) administrations. Reaction frequencies were not significantly different among the GBCM (0.3% gadofosveset trisodium; 0% gadoxetate disodium, 0.06% gadoterate meglumine, 0.08% gadopentetate dimeglumine; P > 0.05). Ten (47.6%) reactions were mild, 10 (47.6%) were moderate, and 1 (4.8%) was severe. The overall reaction frequency peaked during the 6-month transition period from gadopentetate dimeglumine to gadoterate meglumine (0.20%), compared with 0.07% pretransition (P = 0.048) and 0.04% posttransition (P = 0.0095)., Conclusion: Allergic-like reactions to GBCM in children are rare. Gadoterate meglumine has a reaction frequency that does not significantly differ from other GBCMs. During the transition from gadopentetate dimeglumine to gadoterate meglumine, an increase in the frequency of reported allergic-like reactions was observed, likely reflective of the Weber effect.

To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology. Gadolinium presence in brain, femur, kidneys, liver and skin was determined using inductively coupled plasma-mass spectrometry (ICP-MS). No effects of MultiHance on behavior, cognitive function or any other parameter were noted, even for the highest administered cumulative dose (15 mmol/kg). Gadolinium presence was variable across tissues and decreased during the 60-day treatment-free period. The highest levels were noted in the femur and the lowest levels in the brain. Gadolinium presence in juvenile rat brain following single or repeated MultiHance administrations was minimal and non-impactful., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

In the 3 years since residual gadolinium-based contrast agent (GBCA) in the brain was first reported, much has been learned about its accumulation, including the pathway of GBCA entry into the brain, the brain distribution of GBCA and its excretion. Here we review recent progress in understanding the routes of gadolinium deposition in brain structures.

Purpose To determine whether signal intensity (SI) in T1 sequences as a potential indicator of gadolinium deposition increases after repeated administration of the macrocyclic gadolinium-based contrast agents (GBCAs) gadoteridol and gadoterate meglumine in a pediatric cohort. Materials and Methods This retrospective case-control study of children with brain tumors who underwent nine or more contrast material-enhanced brain magnetic resonance (MR) imaging studies from 2008 to 2015 was approved by the local ethics board. Informed consent was obtained for MR imaging. Twenty-four case patients aged 5-18 years and appropriate control patients with nonpathologic MR neuroimaging findings (and no GBCA administration), matched for age and sex, were inculded. SI was measured on unenhanced T1-weighted MR images for the following five regions of interest (ROIs): the dentate nucleus (DN), pons, substantia nigra (SN), pulvinar thalami, and globus pallidus (GP). Paired t tests were used to compare SI and SI ratios (DN to pons, GP to thalamus) between case patients and control patients. Pearson correlations between relative signal changes and the number of GBCA administrations and total GBCA dose were calculated. Results The mean number of GBCA administrations was 14.2. No significant differences in mean SI for any ROI and no group differences were found when DN-to-pons and GP-to-pulvinar ratios were compared (DN-to-pons ratio in case patients: mean, 1.0083 ± 0.0373 [standard deviation]; DN-to-pons ratio in control patients: mean, 1.0183 ± 0.01917; P = .37; GP-to-pulvinar ratio in case patients: mean, 1.1335 ± 0.04528; and GP-to-pulvinar ratio in control patients: mean, 1.1141 ± 0.07058; P = .29). No correlation was found between the number of GBCA administrations or the total amount of GBCA administered and signal change for any ROI. (Number of GBCA applications: DN: r = -0.254, P = .31; pons: r = -0.097, P = .65; SN: r = -0.194, P = .38; GP: r = -0.175, P = .41; pulvinar: r = -0.067, P = .75; total amount of administered GBCA: DN: r = 0.091, P = .72; pons: r = 0.106, P = .62; SN: r = -0.165, P = .45; GP: r = 0.111, P = .61; pulvinar: r = 0.173, P = .42.) Conclusion Multiple intravenous administrations of these macrocyclic GBCAs in children were not associated with a measurable increase in SI in T1 sequences as an indicator of brain gadolinium deposition detectable by using MR imaging. Additional imaging and pathologic studies are needed to confirm these findings. © RSNA, 2017 Online supplemental material is available for this article.

Objectives: To evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine., Methods: Our population included 62 patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model., Results: Group 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (p < 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (p = 0.0735)., Conclusion: There is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur., Key Points: • Neural gadolinium deposition is associated with multiple administrations of less stable GBCAs. • Less stable GBCA effect on subsequent more stable GBCA administrations is undetermined. • Significant increase of DN/MCP was seen in patients with previous gadodiamide exposure. • RC DN/MCP showed a non-significant increase in patients who received previous gadodiamide. • Potentiating effects from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur.

The trans-placental permeability of liposomal Gadolinium (Gd) nanoparticle contrast agents was evaluated in a pregnant mouse model. Pregnant Balb/c mice at 16.5 (±1) days of gestation were imaged using a 3D Spoiled Gradient Echo method at 9.4 T using two contrast agents: a clinically approved Gd chelate, Multihance(®) (gadobenate dimeglumine), and a novel experimental liposomal Gd agent. A Dynamic Contrast Enhancement (DCE) protocol was used to capture the dynamics of contrast entry and distribution in the placenta, and clearance from circulation. A blinded clinical radiologist evaluated both sets of images. A reference region model was used to measure the placental flow and physiological parameters; volume transfer constant (K(trans)), efflux rate constant (K(ep)). The Gd content of excised placentae and fetuses was measured, using inductively coupled plasma mass spectrometry (ICP-MS). MRI images of pregnant mice and ICP-MS analyses of placental and fetal tissue demonstrated undetectably low transplacental permeation of the liposomal Gd agent, while the clinical agent (Multihance) avidly permeated the placental barrier. Image interpretation and diagnostic quality was equivalent between the two contrast agents. Additional testing to determine both maternal and fetal safety of liposomal Gd is suggested.

Objective: The aims of this study were to compare 3 contrast agents and to define feasible doses for quantitative lung perfusion imaging using the dual-bolus approach in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI)., Materials and Methods: Ten healthy volunteers (6 males, 4 females; mean age, 23.5 years) underwent DCE-MRI at 1.5 T using a 3D FLASH sequence. After a prebolus, 3 doses of gadopentetate dimeglumine (Gd-DTPA), gadofosveset, and gadobenate dimeglumine (Gd-BOPTA) were evaluated. Dose regimes were as follows: Gd-DTPA: 3.0 mL, 6.0 mL, and 12.0 mL with 1.5 mL prebolus; gadofosveset: 1.5 mL, 3.0 mL, and 6.0 mL with 0.8 mL prebolus; and Gd-BOPTA: 1.5 mL, 3.0 mL, and 6.0 mL with 0.8 mL prebolus. Pulmonary blood flow (PBF), pulmonary distribution volume, and mean transit time were assessed for each bolus. Region of interest measurements were used to determine the arterial input function (AIF) in the pulmonary trunk and signal intensities in lung parenchyma. Two radiologists independently rated the subjective image quality of the quantitative perfusion maps based on a 4-point Likert scale., Results: Dose-dependent signal saturation effects were observed for all 3 contrast agents concerning AIF and parenchyma measurements. Signal yields were comparable using Gd-BOPTA (AIF, 214.49 arbitrary units [AU]; parenchyma, 41.7 AU) and Gd-DTPA (207.43 AU; 36.3 AU). Gadofosveset showed significantly lower signal yield (165.74 AU; 25.2 AU; p < 0.008). Highest signal increase was observed for Gd-DTPA. Using Gd-DTPA, mean PBF values for the 3 doses (3 mL, 6 mL, 12 mL) in mL/min per milliliter lung volume were 2.9 ± 1.5, 2.4 ± 1.1, and 1.6 ± 1.0. For the 3 doses of gadofosveset (1.5 mL, 3 mL, 6 mL) mean PBF results were 3.1 ± 1.1, 1.9 ± 0.7, and 1.2 ± 0.6. Last, mean PBF values for Gd-BOPTA (1.5 mL, 3 mL, 6 mL) were 3.4 ± 1.7, 2.8 ± 1.3, and 2.0 ± 0.8. Measurements provided consistent values for all perfusion parameters (PBF, pulmonary distribution volume, mean transit time) when compared with reference literature. Contrast dose volume and the applied contrast agent had no relevant effects on the image quality scores., Conclusions: The dual-bolus approach using a 3D FLASH sequence is a feasible tool for quantitative lung perfusion imaging. Small boluses of 3 mL for Gd-DTPA, 1.5 mL for Gd-BOPTA, and 1.5 mL for gadofosveset provide sufficient signal yield for quantitative parenchyma measurements. Using higher boluses falsely lower perfusion values have to be considered due to signal saturation effects. Although gadofosveset yielded the lowest signal, the generated quantitative perfusion maps were of diagnostic quality.

Purpose: Retrospective comparison between gadofosveset trisodium and gadobenate dimeglumine steady state magnetic resonance angiography (SS-MRA) of the thoracic vasculature at 1.5T using signal-to-noise ratio (SNR) and vessel edge sharpness (ES) as markers of image quality., Materials and Methods: IRB approval was obtained. Twenty separate patients each underwent SS-MRA using high-resolution 3D ECG-triggered coronal IR-TFE at 1.5T approximately 3-4 minutes following 10 or 15 mL gadofosveset or 20 mL gadobenate. ROIs were placed in the right atrium, left ventricle, left atrium, ascending aorta, descending aorta, and right pulmonary artery to estimate SNR. Vessel ES was estimated as 20-80% rise distances from line intensity profiles in the left pulmonary vein, ascending aorta, and descending aorta. Data were analyzed using nonpaired Student's t-test (threshold for significance set at P < 0.05)., Results: There was no significant difference in mean SNR for the gadofosveset or gadobenate groups (P values: 0.14 to 0.85). There was no significant difference in mean vessel ES for gadofosveset and gadobenate groups (P values: 0.17 to 0.78)., Conclusion: High quality thoracic SS-MRA can be achieved with gadobenate dimeglumine, similar to that achieved with the blood pool agent gadofosveset trisodium provided that imaging is initiated quickly (3-4 min) after contrast injection.

The approach to imaging patients with kidney disease with iodinated radiocontrast and gadolinium-based contrast has changed dramatically in recent times. The complications of these contrast agents, radiocontrast nephropathy and nephrogenic systemic fibrosis, respectively, underlie the changes in the imaging practice used in these patients. Rather than to completely avoid the use of these contrast agents, one must remain judicious in the choice of imaging modality in this group of patients. A prudent approach would be to (1) identify patients at high risk to develop contrast-related complications, (2) use noncontrast-based imaging techniques in these patients, as long as they are suitably diagnostic and safe and (3) if the risk:benefit ratio of the imaging information favors a contrast-based study, then appropriate prophylactic steps and use of contrast agents with the lowest risk of complication should be used after obtaining informed consent. This will allow one to maximize the diagnostic efficiency while also limiting the adverse effects.

Background: To develop a lipid-stabilized contrast formulation containing gadobenate dimeglumine for clear visualization of the mucosal surfaces of the larynx and trachea for early diagnosis of disease by magnetic resonance imaging., Methods: The contrast formulation was prepared by loading gadobenate dimeglumine into egg phosphotidylcholine, cholesterol, and sterylamine nanoliposomes using the dehydration-rehydration method. The liposomal contrast formulation was ultrasonically nebulized, and the deposition and coating pattern on explanted pig laryngeal and tracheal segments was examined by inductively coupled plasma atomic emission spectroscopy. The sizes of the nebulized droplets were characterized by photon correlation spectroscopy. The contrast-enhanced mucosal surface images of the larynx and trachea were obtained in a 3.0T magnetic resonance scanner using a T1-weighted spectral presaturation inversion recovery sequence., Results: Various cationic liposome formulations were compared for their stabilization effects on the droplets containing gadobenate dimeglumine. The liposomes composed of egg phosphotidylcholine, cholesterol, and sterylamine in a molar ratio of 1:1:1 were found to enable the most efficient nebulization and the resulting droplet sizes were narrowly distributed. They also resulted in the most even coating on the laryngeal and tracheal lumen surfaces and produced significant contrast enhancement along the mucosal surface. Such contrast enhancement could help clearer visualization of several disease states, such as intraluminal protrusions, submucosal nodules, and craters., Conclusion: This lipid-stabilized magnetic resonance imaging contrast formulation may be useful for improving mucosal surface visualization and early diagnosis of disease originating in the mucosal surfaces of the larynx and trachea.

Objective: This study was designed to determine the optimal mixture ratio of gadolinium and iodinated contrast agent for simultaneous direct MR arthrography and CT arthrography., Materials and Methods: An in vitro study was performed utilizing mixtures of gadolinium at six different concentrations (0.625, 1.25, 2.5, 5.0, 10 and 20 mmol/L) and iodinated contrast agent at seven different concentrations (0, 12.5, 25, 37.5, 50, 75 and 92-99.9%). These mixtures were placed in tissue culture plates, and were then imaged with CT and MR (with T1-weighted sequences, proton-density sequences and T2-weighted sequences). CT numbers and signal intensities were measured. Pearson's correlation coefficients were used to assess the correlations between the gadolinium/iodinated contrast agent mixtures and the CT numbers/MR signal intensities. Scatter diagrams were plotted for all gadolinium/iodinated contrast agent combinations and two radiologists in consensus identified the mixtures that yielded the optimal CT numbers and MR signal intensities., Results: The CT numbers showed significant correlation with iodinated contrast concentrations (r = 0.976, p < 0.001), whereas the signal intensities as measured on MR images showed a significant correlation with both gadolinium and iodinated contrast agent concentrations (r = -484 to -0.719, p < 0.001). A review of the CT and MR images, graphs, and scatter diagram of 42 combinations of the contrast agent showed that a concentration of 1.25 mmol/L gadolinium and 25% iodinated contrast agent was the best combination for simultaneous CT and MR imaging., Conclusion: A mixture of 1.25 mmol/L gadolinium and 25% iodinated contrast agent was found to be optimal for simultaneous direct MR arthrography and CT arthrography.

Purpose: To evaluate the biliary enhancement dynamics of the two gadolinium chelates Gd-BOPTA (MultiHance) and Gd-EOB-DTPA (Primovist) in normal healthy subjects., Material and Methods: Ten healthy volunteers were evaluated with both agents by magnetic resonance (MR) imaging at 1.5T using a breath-hold gradient-echo T1-weighted VIBE sequence. The relative signal intensity (SI) differences between the common hepatic duct (CHD) and liver parenchyma were measured before and 10, 20, 30, 40, 130, 240, and 300 min after contrast medium injection., Results: Biliary enhancement was obvious 10 min post-injection for Gd-EOB-DTPA and was noted at 20 min for Gd-BOPTA. At 40 min delay, Gd-BOPTA reached its peak biliary enhancement, but at neither 30 nor 40 min delay was there any significant difference compared with that of Gd-EOB-DTPA. At later delays, the contrast between CHD and liver continued to increase for Gd-EOB-DTPA, whereas it decreased for Gd-BOPTA., Conclusion: The earlier onset and longer duration of a high contrast between CHD and liver for Gd-EOB-DTPA facilitates examination of hepatobiliary excretion. Therefore, Gd-EOB-DTPA may provide adequate hepatobiliary imaging within a shorter time span than Gd-BOPTA and facilitate scheduling at the MR unit. Further studies in patients are required to compare the imaging advantages of Gd-EOB-DTPA and Gd-BOPTA in clinical practice.

Purpose: To test in vitro whether gadolinium-based contrast agents induce fewer toxic effects on renal tubular cells than does an iodinated contrast medium at concentrations used for angiography., Materials and Methods: LLC-PK1 cells were incubated with iomeprol, gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, gadodiamide, and corresponding mannitol solutions for 24 hours at 37 degrees C in two experimental settings: measurements with equally attenuating solutions and measurements with equimolar solutions. Cytotoxicity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, trypan blue testing, and an assay to detect apoptosis and necrosis. Data were analyzed with analyses of variance and post hoc tests., Results: Yielding the same x-ray attenuation, iomeprol-300 and iomeprol-150 at concentrations of 2.34-18.75 mg of iodine per milliliter induced significantly (P < .001) lower inhibition of MTT conversion (74%-102% of undamaged control cells) compared with 15.63-125.00 mmol/L concentrations of the gadolinium-based agents (mean percentages of undamaged control cells: 48%-80%, 50%-87%, 60%-95%, and 56%-92% with gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, and gadodiamide, respectively). At equimolar concentrations (62.5 mmol/L), iomeprol-190 induced a mean extent of inhibition of MTT conversion (69% of undamaged control cells) similar to that induced by gadoterate meglumine (71%) and gadodiamide (70%), whereas gadopentetate dimeglumine and gadobenate dimeglumine induced stronger effects (63% and 64%, respectively; P < .001). At trypan blue testing, there were more dead cells after incubation with 125 mmol/L gadopentetate dimeglumine than after incubation with iomeprol-190 (57% vs 19%, P < .001). The 125 mmol/L gadopentetate and gadobenate formulations induced more necrosis and apoptosis than did gadoterate meglumine, gadodiamide, and iomeprol (mean percentage difference between treated and untreated control cells: for necrosis, +124%, +95%, +17%, -6%, and +3%, respectively; for apoptosis, +34%, +35%, +13%, +4%, and +5%, respectively; P < .001)., Conclusion: At angiographic concentrations, gadolinium-based contrast agents do not induce fewer cytotoxic effects on cultured renal tubular cells than does iomeprol., ((c) RSNA, 2007.)

Background: Gadobenate dimeglumine (Gd-BOPTA) demonstrates superior enhancement of brain tumours in adult patients than Gd-DTPA., Objective: To determine whether Gd-BOPTA has advantages over Gd-DTPA for enhanced MR imaging of paediatric brain and spine tumours., Materials and Methods: Sixty-three subjects, aged 6 months to 16 years, who were enrolled in a prospective, fully blinded, randomized parallel-group phase III clinical trial, received 0.1 mmol/kg doses of either Gd-BOPTA (n=29) or Gd-DTPA (n=34). The MR images were acquired before and within 10 min of contrast agent injection. The primary objective was to compare the difference from pre-dose to post-dose lesion visualization between Gd-BOPTA and Gd-DTPA. Lesion visualization was determined as the sum of individual scores for three criteria of lesion morphological characteristics (lesion border delineation, internal morphology, and contrast enhancement), each assessed qualitatively using 4-point scales. Quantitative evaluation compared changes in lesion-to-background (LBR) and contrast-to-noise (CNR) ratios and per cent enhancement. Monitoring for adverse events and evaluation of vital signs and laboratory values was performed., Results: Pre-dose to post-dose changes in lesion visualization were significantly better for Gd-BOPTA for both lesion level (2.68+/-2.17 vs. 1.05+/-1.90, P=0.0106) and patient level (2.55+/-2.18 vs. 1.14+/-1.68, P=0.0079) comparisons. The mean pre-dose to post-dose change in CNR was greater for Gd-BOPTA (9.13+/-15.36) than Gd-DTPA (2.18+/-9.90), but the difference was only marginally significant (P=0.0779; 95% CI: -0.553, 14.454) because of wide variations of signal intensity between lesions. Similar findings were obtained for LBR and per cent enhancement. No differences between the agents were noted in terms of safety parameters., Conclusions: At an equivalent dose Gd-BOPTA is significantly better than Gd-DTPA for visualization of enhancing CNS tumours in paediatric patients.

Purpose: Different centers and vendors use different sequences and contrast agent application schemes for MR myocardial perfusion imaging. The purpose of this study was to evaluate the role of different sequences, dosages, and injection speeds of contrast media for semiquantitative MR-perfusion assessment., Methods: In a pilot study with 58 consecutive patients three of the most commonly used sequences for MR myocardial perfusion imaging (T1-GrE, GrE-EPI or SSFP) were compared to each other in terms of peak myocardial enhancement and image quality. For the main part of the study dynamic first pass MR perfusion imaging (Philips Intera CV, Best, Tthe Netherlands) was performed in 24 patients using the most favorable sequence from the pilot study (SSFP) after peripheral i.v. administration of Gd-BOPTA during adenosine stress. Two doses (0.05 mmol/kg bw and 0.025 mmol/kg bw) and four different injection speeds (8, 4, 3, 2 ml/s) were used. Signal intensity time curves were determined in the LV and myocardial segments supplied by normal coronary arteries and correlation between LV and myocardial upslope as well as peak enhancement were noted., Results: The SSFP-sequence showed a higher peak enhancement when using 0.05 mmol/kg bw of Gd-BOPTA and a superior image quality for both dosage regimen compared with the other sequences and was consequently applied for the main study. A significant correlation was found between the upslopes in the LV and the myocardium (r square = 0.85, p < 0.001). However, LV and myocardial upslopes were largely independent of the dosage. Myocardial upslope was significantly slower at an injection rate of 2 ml/s compared to 3 and 4 ml/s. Higher Gd-doses led to significantly higher enhancement (p < 0.001)., Conclusion: In healthy myocardial segments, the myocardial upslope is mainly determined from the LV upslope. Both myocardial enhancement and upslope are largely independent from the injection rate of a contrast agent bolus as long as the injection speed is not below 3 ml/s. Myocardial enhancement, however, is dose dependent. Thus, a simple correction for LV upslope allows to normalize a wide variety of input parameters. Differences of myocardial upslope or peak signal intensity after correction should be mainly dependent on blood flow.

Rationale and Objectives: This study was performed to evaluate the relationship between dose levels of contrast medium and image quality in magnetic resonance (MR) angiography of the carotid arteries with fluoroscopically monitored, manually triggered, elliptically ordered image acquisitions., Materials and Methods: Twenty-five patients with clinical indications for angiography of the carotid arteries were examined with MR at 1.5 T by using a fluoroscopically monitored, manually triggered, elliptically ordered pulse sequence with the administration of one of three different volumes of gadolinium-based contrast medium. The signal intensities of the vessel lumen and the surrounding tissues were measured in single partitions at the origin of the common carotid artery, the carotid bifurcation, and the intracranial internal carotid arteries. The contrast-to-noise ratio in these regions of interest also was measured. Maximum intensity projection image quality was appraised for blurring, artifacts, venous enhancement, background suppression, and contrast medium distribution., Results: No artifacts or venous enhancement was observed. The position of the fluoroscopic section affected the distribution of contrast medium along the vessel, as evidenced by the difference between the contrast-to-noise ratio at the origin of the common carotid artery and the ratio at the carotid bifurcation and the intracranial internal carotid arteries (P < .01). The contrast medium dose administered was strongly correlated with image quality (r = 0.90)., Conclusion: Contrast medium dose is related to image quality in MR angiography of the carotid arteries performed with elliptical ordering, fluoroscopic monitoring, and manual triggering.

Objective: This study was conducted to determine the efficacy and safety of four different doses of gadobenate dimeglumine for contrast-enhanced three-dimensional MR angiography of the abdominal aorta and renal arteries., Subjects and Methods: Ninety-four patients with suspected abnormality of the abdominal aorta or renal arteries underwent unenhanced three-dimensional gradient-recalled echo time-of-flight MR angiography and contrast-enhanced MR angiography after the IV injection of one of four doses of gadobenate dimeglumine (0.025, 0.05, 0.1, and 0.2 mmol/kg of body weight). Efficacy was assessed on-site and by two blinded off-site reviewers in terms of change in total diagnostic quality score and diagnostic quality score per vessel segment from baseline unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography. Secondary efficacy end points included lesion count and level of confidence in lesion characterization. Safety assessments comprised adverse event monitoring, physical evaluation, vital signs, ECG, and laboratory investigations., Results: A significant change in the total diagnostic quality score from unenhanced to contrast-enhanced MR angiography was observed at all doses. The change increased with increased dose, plateauing at the 0.1 mmol/kg dose level. More patients with lesions detected and increased reviewer confidence for lesion characterization were noted on contrast-enhanced MR angiography compared with unenhanced MR angiography, although no dose-related trends were observed. All doses were well tolerated, and no significant changes in safety parameters were observed., Conclusion: Gadobenate dimeglumine is an effective and safe agent for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. A dose of 0.1 mmol/kg of body weight appears to be the most suitable.

The aim of this study was to determine the efficacy of Gd-BOPTA-enhanced MRI in liver lesion detection in comparison with unenhanced MRI and dynamic CT. The image sets of 148 of 151 patients enrolled in a multicenter German phase-III trial were evaluated by two independent radiologists unaffiliated with the investigating centers. Patients underwent a routine MRI protocol comprising T2- and T1-weighted spin-echo and T1-weighted gradient-echo (GE) sequences pre and 1 h post 0.1 mmol/kg Gd-BOPTA (Bracco-Byk Gulden, Konstanz, Germany). Additionally, a serial T1-weighted GE scan was performed after administration of the first half of the dose. All patients underwent dynamic contrast-enhanced CT. The evaluation was performed with regard to the number and size of lesions detected per patient by each modality or sequence. Furthermore, all pre CM and pre + post CM image sets were analyzed for number of lesions per patient. Both readers detected significantly more lesions in the contrast-enhanced image set compared with the unenhanced image set (32 and 39 %, respectively; p < 0.0001). While contrast-enhanced CT detected a similar number of lesions to unenhanced MRI, it was clearly inferior to contrast-enhanced MRI (reader 1: p = 0.0117; reader 2: p = 0.0225). Of the T1-weighted scans performed, the dynamic and late T1-weighted GE exams contributed most to the increased lesion detection rate (reader 1: p = 0.0007; reader 2: p = 0.0037). The size of the smallest lesion detected by means of MRI was significantly larger in the pre-CM image sets than in the pre + post CM image sets (reader 1: p = 0.001; reader 2: p < 0.0001). Gd-BOPTA-enhanced MRI detected significantly smaller lesions than contrast-enhanced CT (reader 1: p = 0.0117; reader 2: p = 0.0925). Gd-BOPTA-enhanced MR imaging improves liver lesion detection significantly over unenhanced MRI and dynamic CT.

Purpose: To evaluate gadobenate dimeglumine (Gd-BOPTA) for dynamic and delayed magnetic resonance (MR) imaging of focal liver lesions., Materials and Methods: In 126 of 214 patients, MR imaging was performed before Gd-BOPTA administration, immediately after bolus administration of a 0.05- mmol/kg dose of Gd-BOPTA, and 60-120 minutes after an additional intravenously infused 0.05-mmol/kg dose. In 88 patients, imaging was performed before and 60-120 minutes after a single, intravenously infused 0.1-mmol/kg dose. T1- and T2-weighted spin-echo and T1-weighted gradient-echo images were acquired. On-site and blinded off-site reviewers prospectively evaluated all images. Intraoperative ultrasonography, computed tomography (CT) during arterial portography, and/or CT with iodized oil served as the reference methods in 110 patients., Results: Significantly more lesions were detected on combined pre- and postcontrast images compared with on precontrast images alone (P <. 01). All reviewers reported a decreased mean size of the smallest detected lesion and improved lesion conspicuity on postcontrast images. All on-site reviewers and two off-site reviewers reported increased overall diagnostic confidence (P <.01). Additional lesion characterization information was provided on up to 109 (59%) of 184 delayed images and for up to 50 (42%) of 118 patients in whom dynamic images were assessed. Gd-BOPTA would have helped change the diagnosis in 99 (47%) of 209 cases and affected patient treatment in 408 (23%) of 209 cases., Conclusion: Gd-BOPTA increases liver lesion conspicuity and detectability and aids in the characterization of lesions.

The present article demonstrates pictorially the use of MultiHance (gadobenate dimeglumine, Gd-BOPTA) in dynamic magnetic resonance imaging and is aimed at ensuring that the product is not misconceived as solely a hepatobiliary agent for use in delayed, static magnetic resonance imaging for the improved detection of focal liver lesions. The enhancement patterns of three malignant (hepatocellular carcinoma, cholangiocarcinoma and metastasis) and three benign (hemangioma, focal nodular hyperplasia and adenoma) lesion types are demonstrated. Each was imaged during the dynamic phase of contrast enhancement immediately following the intravenous bolus administration of 0.05 mmol/kg MultiHance. The article demonstrates that the enhancement patterns observed for these relatively common lesions are similar to those reported in the literature after the intravenous bolus administration of conventional, non-specific 'extracellular fluid' contrast agents, and concludes by inferring that MultiHance behaves in the liver as a conventional gadolinium-based agent in the first minutes after administration.

Purpose: To assess preliminarily the efficacy of 0.1 and 0.2 mmol/kg doses of MultiHance for contrast-enhanced magnetic resonance imaging of brain tumors., Methods: Patients were imaged pre-dose using proton density (PD), T2-weighted and T1-weighted spin-echo sequences, and post-dose by repetition of the T1-weighted sequences at 0-15, 15-30, 30-45 and 45-60 min after the completion of MultiHance administration. Qualitative efficacy assessments of the image sets were performed by two blinded neuroradiologists in terms of the level of diagnostic information, the type of additional information provided by post-contrast images, the best post-contrast image set in terms of diagnostic information, the radiological utility of MultiHance, and the detectability of brain metastases. Extensive safety and tolerability controls were performed at 3 and 24 h post-contrast., Results: Additional diagnostic information was available on MultiHance-enhanced images as compared to pre-contrast images for 58.678.9% of patients administered 0.1 mmol/kg MultiHance and 66.1-74.6% of patients administered 0.2 mmol/kg MultiHance. Generally, the early (0 to 30 min) post-contrast image sets were preferred, with a clear superiority at the 15-30 min post-dose time point. In a subgroup of 21 patients with brain metastases, a higher number of lesions was detected in 55.6-66.7% of the cases with 0.1 mmol/kg MultiHance and in 58.3% of the cases with 0.2 mmol/kg MultiHance. Overall, the usefulness of MultiHance was judged as good to excellent in 91.4% of the patients at both dose levels. A total of 12 of 120 patients (10%) reported 15 transient, self-resolving adverse events of mild-to-moderate intensity. No difference between doses was observed in the incidence of adverse events and no laboratory, ECG or vital signs abnormalities were reported., Conclusion: MultiHance is a safe and effective contrast agent for magnetic resonance assessment of brain tumors when administered intravenously at doses up to 0.2 mmol/kg.

Objective: To support the clinical use of gadobenate dimeglumine for injection as an intravascular magnetic resonance imaging contrast medium through an extensive battery of toxicological safety studies., Methods: Single and multiple dose toxicity, reproduction and mutagenicity assessments were carried out in rodents and non-rodents., Results: Initial adverse clinical signs in monkeys were associated with a systemic exposure 34 times higher than that found in humans after 0.1 mmol/kg gadobenate dimeglumine. Good systemic tolerance was observed in repeated dose toxicity studies. Reproductive performance and physical and behavioral development of offspring were unaffected at doses corresponding to 20 times the human dose. Mutagenicity tests excluded any genotoxic potential of gadobenate dimeglumine., Conclusion: Based on the wide margins of safety demonstrated in different species, particularly in primates, gadobenate dimeglumine can be considered as safe in the range of clinical doses recommended for magnetic resonance imaging.

Mechanistic studies regarding the action of gadobenate dimeglumine (Gd-BOPTA/Dimeg; MultiHance) in animals are presented, and the relevance of the results to protocols for MR imaging of the liver are discussed. Gd-BOPTA/Dimeg maintains all the characteristics of an extracellular contrast agent, but owing to a weak affinity for serum albumin, provides in these applications stronger signal intensities than contrast agents without such affinity at the same dose. This property can be taken advantage of for dynamic liver imaging. A unique property of Gd-BOPTA/Dimeg is that the contrast effective ion, Gd-BOPTA2-, enters hepatocytes selectively and reversibly through the sinusoidal plasma membrane using transport mechanisms other than the organic anion transport polypeptide. In a rate-limiting step, the ion is excreted by the multispecific organic anion transporter into the bile. The increase in liver distribution space of Gd-BOPTA2-, as compared to that of purely extracellular contrast agents, is identified as the principal mechanism of normal parenchymal signal enhancement. Microviscosity effects inside hepatocytes add to the relaxation effectiveness of Gd-BOPTA2-, while its presence in the bile and an affinity for intracellular macromolecules play subordinate roles only. Gd-BOPTA2- persists in hepatocytes beyond the times characteristic of dynamic imaging, providing delayed-phase contrast between normal hepatocytes and tumor cells. As a result, the conspicuity of small focal lesions and thus their detection is improved. Additionally, Gd-BOPTA/Dimeg allows sites of abscesses and systemically damaged tissue to be distinguished from healthy liver. Taken together these mechanistically-supported properties qualify the product as a versatile general MR contrast agent with added merits in liver imaging.

Objectives: To assess in animals the pharmacological tolerability for intravascular gadobenate dimeglumine., Results: Cardiovascular effects: In healthy animals no relevant effects were observed apart from slight and transient increases in cardiac output and decreases in systemic vascular resistance. In pigs with myocardial ischemia: doses up to 3.0 mmol/kg caused dose-dependent decreases in heart rate, systemic vascular resistance and mean arterial blood pressure along with transient increases in cardiac output. In vitro: Myocardial contractility was slightly depressed after direct exposure to a 30 mM solution. Respiratory effects in healthy pigs: no effects after 1.0 mmol/kg i.v. Effects on the central nervous system: In healthy animals: gadobenate dimeglumine, 1.0 mmol/kg i.v, did not penetrate nor impair the blood-brain barrier in rats and did not affect behavior, motor coordination or EEG. In pathological models: even in the presence of an osmotically disrupted blood-brain barrier, brain penetration of gadobenate was poor and no signs of epileptogenic potential were evident. Effects on blood: No hemolytic potential was observed. Plasma coagulation was slightly affected in vitro but not in vivo. Effects on kidney and liver function: Transient increases in diuresis, without effects on blood and urine enzymes were observed at doses of 1.25 and 2.5 mmol/kg., Conclusions: The clinical use of gadobenate dimeglumine as an intravascular magnetic resonance imaging contrast agent is strongly supported by the good tolerability of the product in healthy and pathological animal models.

Objective: Evaluation of the pharmacokinetic behavior of gadobenate dimeglumine, a new multipurpose parenteral contrast agent for magnetic resonance imaging., Methods: The pharmacokinetics were evaluated in rats, rabbits, dogs and monkeys after intravenous injections of non-labelled gadobenate dimeglumine and, for biodistribution studies, 153Gd-labelled gadobenate dimeglumine. Assays were performed by high performance liquid chromatography, X-ray fluorescence and gamma spectrometry. The binding of gadobenate ion to animal and human serum albumin was studied by equilibrium dialysis., Results: After intravenous injection gadobenate dimeglumine distributes into plasma and extracellular fluid as well as into the intrahepatocytic space. Gadobenate ion is cleared from plasma by renal and biliary excretion. It does not accumulate in specific tissues, except temporarily in tissues related to its elimination. Gadobenate ion is not metabolized. Its binding to plasma proteins is too weak to be detected by equilibrium dialysis., Conclusions: Gadobenate dimeglumine combines the properties of an extracellular-fluid agent with those of a hepatobiliary agent. Its complete elimination and biological stability satisfy the requirements for its safe use in humans.

Objective: The purpose of the study was to evaluate the safety and efficacy of Gd-BOPTA for liver imaging and to determine the most appropriate clinical dose to administer., Methods: Gd-BOPTA was administered at a dose of 0.05 (group A), 0.1 (group B), or 0.2 (group C) mmol/kg to 201 patients suspected of having malignant liver tumors who had been referred for magnetic resonance imaging. Dynamic phase images (T1-weighted gradient echo sequences obtained during breath-hold), images obtained within 10 min of Gd-BOPTA injection (spin echo images) and delayed images obtained at 40-120 min after Gd-BOPTA injection (T1-weighted spin echo and gradient echo sequences during breathhold) were acquired. All post-contrast images were compared with pre-contrast images (T1- and T2-weighted sequences) obtained immediately prior to Gd-BOPTA administration. Safety was assessed in terms of the incidence of adverse events., Results: The contrast efficacy for the dynamic study was classified as ( ) in 39.7% (27/68), 55.4% (36/65), and 47.0% (31/66) for groups A, B, and C, respectively. The contrast efficacy within 10 min of the injection was classified as ( ) in 7.6% (5/66), 16.9% (11/65), and 12.5% (8/64) for groups A, B, and C, respectively. The contrast efficacy at 40-120 min post-injection was classified as ( ) in 4.4% (3/68), 21.5% (14/65), and 20.0% (13/65) for groups A, B, and C, respectively with significant differences noted between groups A and B and groups A and C. As regards safety, the overall incidence of adverse reactions was 3.5% (7/199)., Conclusion: Gd-BOPTA is a safe and efficacious contrast agent for use in both dynamic phase imaging and delayed (40-120 min) static imaging. A dose of 0.1 mmol/kg Gd-BOPTA appears to be the ideal dose for use in liver imaging in Japan.

Rationale and Objectives: To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment., Methods: The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1., Results: Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+., Conclusions: Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

Purpose: Two gadolinium chelates with partial hepatobiliary excretion, Gd-BOPTA and Gd-EOB-DTPA, and one gadolinium chelate with exclusively renal excretion, Gd-HP-DO3A, were compared on MRI at 1.5 T. The time course of enhancement for normal liver, gallbladder, spleen, kidney, and muscle was specifically examined in the rhesus monkey., Method: Four animals were evaluated with each agent for a total of 12 MR studies. Breath-hold and non-breath-hold T1 weighted scans were acquired prior to and 1, 2, 3, 4, 5, 15, 30, 45, 60, 75, and 90 min after intravenous contrast medium injection. The same contrast dose, 0.1 mmol/kg, was used for all studies. Images were analyzed by region-of interest measurements., Results: Both hepatobiliary gadolinium chelates achieved sustained enhancement of normal liver parenchyma, superior in magnitude to that following Gd-HP-DO3A injection. On sans 45-90 min following injection, liver enhancement with Gd-BOPTA was superior to that with Gd-EOB-DTPA. This difference was, however, not statistically significant. Liver enhancement decreased more rapidly on delayed scans with Gd-EOB-DTPA than with Gd-Bopta, a result that was statistically significant. Excretion of contrast agent into the gallbladder was noted with both hepatobiliary agents but not with Gd-HP-DO3A., Conclusion: Enhancement of normal liver parenchyma peaks at a later time after injection with Gd-BOPTA than with Gd-EOB-DTPA. However, the maximum percent enhancement is comparable when (as in the current evaluation) the two agents are compared at the same dose (0.1 mmol/kg). This finding supports the choice of optimal imaging time post contrast agent administration (for delayed scans) in clinical trials of 20-45 min post injection with Gd-EOB-DTPA and 60-120 min post injection with Gd-BOPTA.

Depiction of small-bowel pathologic conditions was optimized with use of a negative luminal contrast agent, spectral fat suppression, and gadolinium enhancement in an excised gut phantom. The method was applied in nine patients in conjunction with standard enteroclysis examinations. Bulk susceptibility effects of oral magnetic particles were canceled with use of a diamagnetic methylcellulose suspension. In the ileum, fat suppression and contrast between bowel wall and lumen was judged good or excellent in eight and nine patients, respectively. In eight of nine patients, additional mesenteric findings were depicted.

Rationale and Objectives: The authors compared the cardiovascular effects of gadodiamide injection and gadopentetate dimeglumine., Methods: Gadodiamide injection or gadopentetate dimeglumine, each at doses of 0.3 or 1.5 mmol per kilogram of body weight, or saline volume control was administered intravenously in the cephalic vein of anesthetized dogs. Hemodynamic parameters, electrocardiographic parameters, and peripheral flow were measured., Results: Neither the low or high dose of gadodiamide injection caused statistically significant (P < .05) changes in any of the measured cardiovascular parameters. High doses of gadopentetate dimeglumine, however, significantly decreased left ventricular and systemic blood pressure and significantly depressed left ventricular contractility (P < .05)., Conclusion: Gadodiamide injection caused no observable cardiovascular effects, whereas high doses of gadopentetate dimeglumine caused cardio-depressive and hypotensive effects.

The optimum infusion timing and k-space ordering for obtaining gadolinium-enhanced three-dimensional MR angiograms was determined through computer modeling using temporal contrast characteristics obtained from patient gadolinium infusion data. The effects of bolus timing were evaluated by varying the relationship between peak intravascular gadolinium concentration and the time at which the center of k space was acquired (tck) for sequential and centric acquisition techniques. Flow phantom experiments were performed to validate the theoretical computations. Gadolinium concentration at the time of central k-space acquisition determines intravascular signal intensity. Artifacts, including vessel broadening and edge ringing, depend on the order in which k space is collected and on how rapidly the gadolinium concentration changes. Artifacts are greatest when the center of k space is acquired before the intravascular gadolinium peak. Application of the optimal infusion timing results in preferential arterial enhancement with a minimum of artifacts in patients undergoing MR angiography.

Purpose: To quantify regional cerebral blood volume (rCBV) on the basis of the enhancement of blood proton relaxation rates after intravenous administration of gadopentetate dimeglumine., Methods: A series of sequential MR images on one section was recorded during bolus transit with a standard fast low-angle shot sequence. The signal-intensity curves were converted into corresponding concentration-time curves from which rCBV images were calculated., Results: The functional parameter images of rCBV were calculated pixel-by-pixel for two patients who had received a 1-second bolus injection of 1 mmol of gadopentetate dimeglumine. In a larger series of 62 patients, a mean blood volume of 4.6 +/- 1.6 vol% was determined for normal brain tissue., Conclusions: The relaxing effect of a contrast agent can be used to determine blood volume quantitatively. The results are in agreement with those obtained by nuclear medicine techniques. The proposed method requires no special hardware, and can thus be implemented on clinical MR scanners.

Purpose: To develop and evaluate a sequence for breath-hold three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography of the abdominal aorta., Materials and Methods: In 63 patients, the abdominal aorta and its branches were imaged for 29, 43, or 58 seconds with breath holding. A fast spoiled gradient-echo sequence was used at 1.5 T during infusion of 42 mL of a gadolinium chelate. Correlation with conventional angiography was performed in 19 patients. MR image quality (signal-to-"total" noise ratio [S/N*]) with breath holding was compared with that with free breathing (104 patients)., Results: With breath-hold gadolinium-enhanced MR angiography, renal, celiac, and superior mesenteric artery occlusive disease was graded appropriately in 15 of 19 patients, and 10 of 11 accessory renal arteries were depicted correctly. Renal artery branches were visualized in 86 of 95 kidneys on breath-hold images compared with only 84 of 236 kidneys with free breathing (P < .001). Distal renal artery S/N* was 3.1 with breath holding and 2.1 with free breathing (P < .001)., Conclusion: Breath holding statistically significantly improves three-dimensional gadolinium-enhanced MR angiography of the renal, celiac, and superior mesenteric arteries.

Purpose: To prospectively correlate dynamic contrast enhancement at magnetic resonance (MR) imaging with mammographic and pathologic features of suspect breast lesions., Materials and Methods: Forty-nine patients with 51 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging at 1.5 T, as well as excisional biopsy or cyst aspiration., Results: Twenty-two of 22 (100%) invasive carcinomas 8 mm or more in diameter, including three (12%) not evident on dense mammograms, enhanced 2.0 or more times the unenhanced intensity. One of three predominantly ductal carcinomas in situ and 10 of 26 (38%) benign lesions enhanced 2.0 or more times. Time-intensity curves were not statistically significantly different among enhancing carcinomas, fibroadenomas, or other benign lesions and showed no statistically significant correlations with pathologic size, nodal status, or hormone receptor status of invasive carcinomas., Conclusion: MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

Purpose: To quantify the rate of adverse reactions to gadopentetate dimeglumine., Materials and Methods: Magnetic resonance (MR) imaging was performed in 15,496 patients in April-September 1992. Data were collected before and after intravenous administration of 0.1 mmol/kg gadopentetate dimeglumine., Results: Adverse reactions occurred in 2.4% (n = 372) of patients. Symptoms abated the same or next day in 94.1% (n = 350). Whereas onset occurred within 30 minutes after injection in 49.7% (n = 185), onset occurred more than 1 hour after injection in 44.9% (n = 167). Two serious adverse reactions occurred and were attributed to underlying disease. The rate of adverse reaction was 3.7% in patients with a history of asthma (31 of 831 patients) or allergy (144 of 3,860 patients). Patients with previous reactions to an MR imaging or iodinated contrast agent had an adverse-reaction rate in this study of 21.3% (16 of 75) and 6.3% (54 of 857), respectively. The rate of adverse reaction was 2.2% when gadopentetate dimeglumine was administered slowly and 2.9% when it was administered rapidly., Conclusion: Findings confirm the safety of gadopentetate dimeglumine.

Purpose: To compare the degree of MR contrast enhancement of 0.5 T and 2.0 T in various brain tumors., Methods: MR images were studied prospectively in each of 31 patients with brain tumors (11 gliomas, 6 meningiomas, 6 neurinomas, and 8 others) before and after intravenous injection of gadopentetate dimeglumine. In every patient, both 0.5-T and 2.0-T MR studies were done within 1 week. Each patient received an initial standard dose (0.1 mmol/kg) of gadopentetate dimeglumine, followed by a subsequent 0.1-mmol/kg dose (total, double dose) in MR of each field strength. MR was done before and after each injection of the contrast agent. Degree of contrast enhancement in the lesions was assessed both visually and quantitatively., Results: With standard-dose study, the tumor enhancement was visually stronger at 2.0 T than at 0.5 T in 9 gliomas. In extraaxial tumors there was visually no or minimal difference between 0.5 T and 2.0 T. Overall mean contrast-enhancement ratio and tumor and brain contrast-to-noise ratio were higher at 2.0 T than at 0.5 T by 53% and 108%, respectively. The double-dose study showed higher contrast-enhancement ratio and contrast-to-noise ratio than the standard-dose study at both field strengths, and the differences between 0.5 T and 2.0 T were almost similar to those of the standard-dose study. The degree of contrast enhancement with the standard dose at 2.0 T was comparable to that of the double dose at 0.5 T in most intraaxial tumors., Conclusion: The results suggest that effect of contrast enhancement increases with the field strength. Therefore, reevaluation of optimal doses of contrast media may be needed in a variety of brain lesions at each field strength.

The purpose of this investigation was to compare the sensitivity and safety of high dose gadoteridol (Pro Hance) with routine dose gadopentetate dimeglumine (Magnevist) in the detection of intracranial metastases on magnetic resonance imaging (MRI) when a solitary intracranial lesion was detected on contrast-enhanced cranial computed tomography (CT). Four patients, each with a solitary intracranial metastasis demonstrated on contrast-enhanced CT were studied prospectively with both 0.3 mmol/kg gadoteridol and 0.1 mmol/kg gadopentetate dimeglumine. Images were acquired before and immediately following contrast administration. Both of the MR studies were performed between two and six days of each other and within 1 wk of the cranial CT. Scan parameters and injection rates were identical on both occasions. Patient monitoring for the gadoteridol study included physical examination, vital signs and laboratory tests at several pre-determined times. Eighteen total metastases were demonstrated on MRI compared to the four on CT. Seven were visualized on the unenhanced MR images, nine on the scans using gadopentetate dimeglumine, and all eighteen on the scans using gadoteridol. Additional lesions were seen on the gadoteridol images in all four patients. No adverse events attributable to contrast media occurred. No significant changes in vital signs or laboratory values occurred.

A nonionic (gadodiamide injection) and an ionic (gadopentetate dimeglumine) contrast medium were compared for their effect on hemodynamics in the anesthetized, open-chest dog. Both agents were administered i.v. over 15 s at dosages of 1.0 and 1.5 mmol/kg, in randomized order. Both contrast agents resulted in transient but statistically significant decreases in aortic pressure, left ventricular pressure, indices of left ventricular contractility and relaxation, and systemic and pulmonary vascular resistance, and increases in aortic blood flow. At each dosage investigated, the changes associated with the administration of gadodiamide injection were of significantly smaller magnitude than those seen after gadopentetate dimeglumine and returned to preadministration levels sooner. The results from this study confirm that gadodiamide injection produces less severe alterations in hemodynamics than gadopentetate dimeglumine.

VX-2 tumors growing in hind legs of New Zealand White rabbits (n = 4) were exposed to thermal neutrons for 40 min (2.1 x 10(12) neutrons cm-2) while one of two hind leg tumors of each rabbit was infused continuously with meglumine gadopentetate through a branch of the left femoral artery. The contralateral (uninfused) tumors served as controls. Although no differential distribution of gadolinium was achieved between the tumor and its adjacent normal tissue, the gadolinium concentration in the infused tumor was approximately 5-6 fold higher than that in the contralateral tumor. Growth of gadolinium-infused tumors was significantly inhibited compared to that of control tumors (P < 0.05) between the 16th and 23rd days after treatment.