Macrocyclic Contrast Agents Research Articles

Brain deposition of gadobutrol in children—a cross-sectional and longitudinal MRI T1 mapping study

ObjectivesDepositions of linear gadolinium-based MRI contrast agents are readily visible in T1-weighted MRIs of certain brain regions in both adults and children. Macrocyclic contrast agents such as gadobutrol have so far escaped detection by qualitative MRI in children. This study aimed to assess whether there is evidence for deposition of gadobutrol in children using quantitative T1 mapping.MethodsThis retrospective study included patients, naive to other gadolinium-based contrast agents than gadobutrol, who had received gadobutrol as part of a clinically indicated MRI. For each patient, T1 relaxation times at 3 T were measured using single-shot T1 mapping at two time points. In each of six brain regions, age-adjusted T1 relaxation times were correlated with a number of previous gadobutrol administrations. To combine interindividual, cross-sectional effects with intraindividual, longitudinal effects, both linear mixed model and generalized additive mixed model were applied.ResultsOne hundred four examinations of 52 children (age median 11.4, IQR 6.3–15, 26 female) with a median of 7 doses of gadobutrol in the history of their neurological or neurooncological disease were included. After correction for age and indeterminate disease-related effects to T1 time, a negative correlation of T1 time with the number of gadobutrol doses administered was observed in both mixed models in the putamen (beta − 1.65, p = .03) and globus pallidus (beta − 1.98, p = .012)ConclusionsThe results indicate that in children, gadobutrol is deposited in the globus pallidus and putamen.Key Points• Previous gadobutrol administration correlates with reduced T1 relaxation times in the globus pallidus and putamen in children.• This decreased T1 might be caused by gadobutrol retention within these gray-matter nuclei.

Effects of gadodiamide and gadoteric acid on lung tissue: A comparative study.

We set out to investigate the effects of gadodiamide and gadoteric acid, used for magnetic resonance imaging, on the lungs. In this study, 32 male Sprague Dawley rats were used. These were allocated into four groups; The first group (control) was untreated. The second group received isotonic saline on the first and fourth days of the week for 5 weeks. Following the same schedule, the third and fourth groups received a total of 2 mg/kg gadodiamide and gadoteric acid, respectively, in place of saline. The alveolar Wall thickness was evaluated. Gadodiamide and gadoteric acid significantly increased the numbers of collagen-3 and caspase-3 positive cells in the lung tissue (p < 0.05). In addition, these two substances increased the alveolar Wall thickness (p < 0.05). Furthermore, they increased the levels of malondialdehyde and glutathione (p < 0.05). This study demonstrates that both linear and macrocyclic contrast agents are toxic for the lungs in rats.

Use of Real-Life Safety Data From International Pharmacovigilance Databases to Assess the Importance of Symptoms Associated With Gadolinium Exposure.

ObjectiveRecent scientific publications have reported cases of patients who complained from a variety of symptoms after they received a gadolinium-based contrast agent (GBCA). The aim of this study was to appreciate the importance of these clinical manifestations in the overall population by assessing the weight of “symptoms associated with gadolinium exposure” (SAGE) among the bulk of safety experiences reported to major health authorities.Materials and MethodsSymptoms associated with gadolinium exposure were identified from a review of the scientific literature, and the corresponding preferred terms were searched in each system organ class (SOC) category recorded in the European and North American pharmacovigilance databases EudraVigilance (EV) and FDA Adverse Event Reporting System (FAERS), respectively. The numbers of SAGE per preferred term, and cumulatively per SOC, were recorded and their weights in the overall spectrum of adverse events (AEs) were determined for each GBCA.ResultsThe analysis of the selected AEs revealed a significantly higher SAGE weight for gadobenate dimeglumine (EV: 25.83%, FAERS: 32.24%) than for gadoteridol (EV: 15.51%; FAERS: 21.13%) and significantly lower SAGE weights for gadobutrol (EV: 7.75%; FAERS: 13.31%) and gadoterate meglumine (EV: 8.66%; FAERS: 12.99%). A similar ranking was found for most of the SOCs except for “nervous system disorders,” probably owing to a limitation in the methods of data selection. Furthermore, this analysis showed a greater percentage of reports mentioning a decrease in the quality of life of the patients when they were exposed to gadobenate dimeglumine or gadoteridol than to gadobutrol or gadoterate meglumine.ConclusionThis study showed that SAGE represent a significant percentage of the bulk of AEs reported to the health authorities for each GBCA. It provided real-life arguments suggesting that SAGE may be more prevalent with linear than macrocyclic GBCAs and that gadoteridol may present a higher SAGE risk than the other macrocyclic contrast agents.

Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention.

Radiologists have been administering gadolinium-based contrast agents (GBCA) in magnetic resonance imaging for several decades, so that there is abundant experience with these agents regarding allergic-like reactions, nephrogenic systemic fibrosis (NSF) and gadolinium retention in the brain. This review is based on a selective literature search and reflects the current state of research on acute adverse effects of GBCA, NSF and brain retention of gadolinium. Due to the frequent use of GBCA, data on adverse effects of these compounds are available in large collectives. Allergic-like reactions occurred rarely, whereas severe acute reactions were very rarely observed. Systemic changes in NSF also occur very rarely, although measures to avoid NSF resulted in a significantly reduced incidence of NSF. Due to gadolinium retention in the body after administration of linear MR contrast agents, only macrocyclic preparations are currently used with few exceptions. Clear clinical correlates of gadolinium retention in the brain could not be identified so far. Although the clinical added value of GBCA is undisputed, individual risks associated with the injection of GBCA should be identified and the use of non-contrast enhanced MR techniques should be considered. Alternative contrast agents such as iron oxide nanoparticles are not clinically approved, but are currently undergoing clinical trials. GBCA have a very good risk profile with a low rate of adverse effects or systemic manifestations such as NSF. Gadolinium retention in the brain can be minimized by the use of macrocyclic GBCA, although clear clinical correlates due to gadolinium retention in the brain following administration of linear GBCA could not be identified yet. · Acute adverse effects are predominantly mild/moderate, rarely severe reactions occur.. · International guidelines resulted in significant reduction of nephrogenic systemic fibrosis.. · Application of macrocyclic contrast agents minimizes gadolinium retention in the brain.. · Bäuerle T, Saake M, Uder M. Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention. Fortschr Röntgenstr 2021; 193: 1010 - 1018.

Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis.

Background Despite the wide use of gadolinium-based contrast agents (GBCAs) for enhanced MRI, their neurochemical and behavioral consequences, if any, remain poorly understood. Purpose To investigate the effect of repeated exposure to a linear or macrocyclic GBCA on gadolinium retention in the central and peripheral nervous system of rats and to assess the functional implications of such retention on hippocampal neurogenesis and sensory and cognitive processing. Materials and Methods Seventy male Sprague-Dawley rats (4 weeks old) received intraperitoneal injections of gadoterate meglumine (0.6 or 2.5 mmol per kilogram of body weight), gadodiamide (0.6 or 2.5 mmol/kg), or saline daily for 20 days (February 2018-March 2019). The 5-bromo-2'-deoxyuridine injections were administered every 3 days to determine the number of proliferating cells and the number of newly maturing neurons in the hippocampus. Sensory and cognitive behavioral tests were performed to assess the effect of GBCAs on pain sensitivity and spatial working memory function, respectively. Finally, inductively coupled plasma mass spectrometry analysis was used to quantify gadolinium retention in the brain, spinal cord, and peripheral nerves 24 hours after the last GBCA administration. One-way and mixed-design analyses of variance were used for statistical analysis. Results All GBCAs resulted in significant gadolinium retention in central and peripheral nervous tissues (1.8-333.2 nmol Gd/g tissue). Pain hypersensitivity to thermal and mechanical stimuli (P < .001) was observed after gadodiamide exposure in rats but not after gadoterate meglumine exposure. Rats injected with both GBCAs showed no changes in spatial working memory or in hippocampal cell proliferation and maturation. Conclusion Gadolinium was retained in the spinal cord and peripheral nerves in rats exposed to multiple administrations of linear and macrocyclic contrast agents. Gadodiamide (linear contrast agent) but not gadoterate meglumine (macrocyclic contrast agent) led to pain hypersensitivity, but neither affected spatial working memory performance, hippocampal cellular proliferation, or hippocampal neurogenesis. © RSNA, 2020 See also the editorial by Radbruch in this issue.

Contrast media- Guidelines for practical use

Contrast agents have become an indispensable part of everyday life in diagnostic radiology. In multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI), they provide essential diagnostic information, especially for vascular, inflammatory or oncologic diseases, which otherwise could not be answered. The two most important groups are iodine- and gadolinium-containing contrast agents. Rare side effects include PC-AKI (post-contrast acute kidney injury); more common are allergic and chemotoxic reactions. Since the introduction of guidelines, nephrogenic fibrosis has not been reported anymore, whereas gadolinium deposition in the central nervous system (CNS) has become anew topic. Concerning contrast media use in patients with reduced renal function, at aeGFR threshold of <45 ml/min or <30 ml/min, hydration and areview of indication for enhanced MDCT, depending on the application, is recommended. Low kV and DE-scan protocols with MDCT can help to reduce the amount of iodinated contrast agents. In MRI examinations, only macrocyclic contrast agents should be used for enhanced MRI exams. There has to be acareful risk-benefit analysis with enhanced studies in pregnancy, during lactation and in the pediatric population. Patient information and legal aspects with nonapproved indications are indispensable parts of daily clinical routine. The continuous updating and broadening of knowledge regarding the appropriate use of the various contrast agents has to be an integral part of clinical diagnostic radiology.

Age, But Not Repeated Exposure to Gadoterate Meglumine, Is Associated With T1- and T2-Weighted Signal Intensity Changes in the Deep Brain Nuclei of Pediatric Patients.

Current findings on gadolinium deposition in the pediatric brain due to repeated exposure to macrocyclic contrast agents are inconclusive and possibly confounded by brain maturation processes. We evaluated the longitudinal effects of repeated gadoterate meglumine exposure (Dotarem; Guerbet, Villepinte, France) on the T1- and T2-weighted signal intensity (SI) in pediatric patients, and assessed the magnitude of age-related increase in T1-weighted (and decrease in T2-weighted) SI in a control cohort without prior gadolinium exposure. In this retrospective, double-cohort study, magnetic resonance imaging (MRI) data of 24 patients (0.7-16.4 years, M = 5.74, SD = 4.15) who received at least 10 doses of exclusively gadoterate meglumine were included in the longitudinal study. The MRI data of 190 controls (age range, 1-20 years; 10 patients/bin; bin width, 1 year) without any prior gadolinium-based contrast exposure were included in the control, cross-sectional study to assess the age-dependent SI changes in the regions of interest (ROIs). We measured SI (native), T1-weighted gradient echo, and T2-weighted fast spin-echo of 12 deep brain nuclei. The ROIs were measured at each of the first 11 MRI examinations of the contrast-exposed patients and in the control subject's MRI. Regions of interest's SIs, normalized by the pons, were analyzed with mixed effects models, accounting for the potential confounding factors, such as radiotherapy and chemotherapy. The number of gadoterate meglumine administrations had no effect on the SI increase in any of the ROIs (all P > 0.05), but age significantly correlated with increased SI in T1-weighted globus pallidus (GP; P < 0.01) and caudate (P < 0.05), and with decreased SI in T2-weighted GP (P < 0.001) and dentate nucleus (P < 0.005) in the contrast-exposed group. The cross-sectional analyses of the control cohort showed a significant age-dependent T1-weighted SI increase in multiple ROIs, including the GP and caudate, and decrease in the T2-weighted GP and dentate nucleus (P < 0.05). Repeated exposure to gadoterate meglumine was not associated with brain hyperintensity in the pediatric patients, whereas age importantly contributed to the SI changes in several deep brain nuclei.

Increased signal intensities and gadolinium levels in the brain after administration of gadolinium-based MR contrast agents : Clinical observations and results from preclinical research

Numerous clinical MRI studies have been published that describe an association between the repeated administration of (linear) gadolinium-based contrast agents and increased signal intensity in certain brain areas. In November 2017, the European Commission suspended the use of some of these contrast agents. The background for this decision, both regulatory and scientific, are presented and discussed. The regulatory decisions are evaluated and the clinical and preclinical literature is discussed. Differences in the structure and stability of gadolinium-based contrast agent molecules explain the observed increased signal intensities in individual brain regions (e. g. dentate nucleus) after administration of multiple doses of linear contrast agents. This phenomenon was not observed after administration of multiple doses of macrocyclic contrast agents. Preclinical studies have confirmed these results. To date, no clinical symptoms have been confirmed to be associated with the increased signal intensity or gadolinium presence in the brain.

Diffusion-weighted imaging of the dentate nucleus after repeated application of gadolinium-based contrast agents in multiple sclerosis

ObjectiveOver the last years several studies reported an increased signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted images after repeated application of gadolinium-based contrast agents (GBCAs), suggesting gadolinium deposition. The aim of this study was to investigate with diffusion-weighted MRI possible tissue abnormalities of the DN in multiple sclerosis (MS) patients. Material and methodsWe retrospectively identified seventeen patients with at least six contrast-enhanced MRI examinations by using the linear GBCA gadopentate dimeglumine and twenty-three patients with the exclusive use of the macrocyclic contrast agent gadoterate meglumine followed by another 3 Tesla MRI scan including unenhanced T1-weighted and diffusion-weighted images. ResultsIn the linear GBCA group, we found significant differences of the DN-to-pons SI ratio on unenhanced T1-weighted images (1.13 ± 0.05) when compared to the macrocyclic GBCA group (0.97 ± 0.03; p < 0.001). However, we found no significant differences between apparent diffusion coefficient (ADC) values of the DN in both groups (linear GBCA group: 0.82 ± 0.04 × 10−3 mm/s2; marcocyclic GBCA group: 0.79 ± 0.04 × 10−3 mm/s2; p = 0.15). ConclusionsOur results do not suggest that there is any difference in ADC values in the T1-hyperintense DN, which does not indicate a difference in tissue integrity between patients exposed to macrocyclic or linear GBCAs.

Synthesis of a gadolinium based-macrocyclic MRI contrast agent for effective cancer diagnosis

BackgroundGadolinium-based contrast agents are widely used as a contrast agent for magnetic resonance imaging. Since gadolinium ions are toxic, many chelators are developed to bind gadolinium ions to prevent free gadolinium-associated disease. However, many reports indicated that linear chelator-based contrast agents are associated with nephrogenic systemic fibrosis (NSF) in patients with low kidney function. Therefore, the demand for stable macrocyclic chelator-based contrast agent is now increasing.Method1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) was conjugated to lactobionic acid (LBA) through DCC-NHS coupling reaction. Gd3+ (gadolinium ion) was chelated to 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate-lactobionic acid (DOTA-LAE) and free Gd3+ was removed using a cation exchange column. In vitro cytotoxicity of contrast agent towards normal cells was measured using MTT assay. For in vivo MR imaging, contrast agents were intravenously injected to tumor-bearing mice and imaged by a MR imaging scanner.ResultsThis new macrocyclic gadolinium-based contrast agent showed enhanced in vitro paramagnetic properties compared to Gadovist. In addition, Gd-DOTA-LAE showed a 29% increased contrast enhancement of tumor tissue compared to normal tissue within 20 min past IV injection.ConclusionsWe developed a new macrocyclic T1-weighted MR contrast agent. This new contrast agent offers various opportunities for cancer detection and diagnosis.

The effect of gadolinium-based contrast agents on rat testis.

Previous studies have reported that repeated administrations of linear gadolinium-based contrast agents lead to their accumulation in the brain and other tissues in individuals with normal renal functions. The purpose of this prospective animal study was to investigate the effect of multiple administrations of macrocyclic ionic (gadoteric acid) and linear nonionic (gadodiamide) gadolinium-based contrast agents (GBCAs) on rat testis tissue and to compare these molecules in terms of tissue damage. Thirty-two male Sprague-Dawley rats were kept without drugs for 5weeks after administration of 0.1mmol mg-1 kg-1 (0.2ml/kg) gadodiamide and gadoteric acid for 4days over 5weeks. Biochemical, histopathological and immunohistochemical changes in testis tissue were evaluated at the end of 10weeks. When used in repeated clinical doses, gadolinium was observed to increase apoptosis in the Leydig cells of the rat testis, and to increase serum Ca+2 levels and reduce testosterone levels (p<.05). Although the difference was not statistically significant, a greater loss of spermatozoa and immature germinal cell accumulation were observed in the seminiferous tubule lumen in the GBCA groups compared with the control and saline groups (p>.05). Both linear and macrocyclic contrast agents have toxic effects on testis tissue, irrespective of the type of drug.

Changes in signal intensity in the dentate nucleus at unenhanced T1-weighted magnetic resonance imaging depending on class of previously used gadolinium-based contrast agent.

Signal increase on T1-weighted magnetic resonance imaging (MRI) in the dentate nucleus has been reported in adults after multiple injections of gadolinium-based contrast agents. Linear contrast agents are more prone to cause this increase. Studies in children are still rare and focus mostly on the analysis of one single agent. To compare signal intensity chances in children after more than four injections of either only linear or only macrocyclic contrast agents. Seventy children (examined from October 2001 to February 2016) were included in this retrospective study. Signal intensities in the dentate nucleus and pons were measured on non-enhanced T1-weighted images from the first and last MRI scans. A two-sample t-test compared the dentate nucleus-to-pons signal intensity ratio differences for linear versus macrocyclic gadolinium-based contrast agent applications and also the number of applications (4-8, 9-12 or >12). Patients' charts were analysed to evaluate potentially associated neurological symptoms. Patients had contrast-enhanced MRI using either only linear (n=16) or only macrocyclic (n=54) gadolinium-based contrast agents. In patients with >12 injections, dentate nucleus-to-pons signal intensity ratio was statistically different concerning the contrast agent class (0.16±0.125 for macrocyclic vs. 0.0005±0.13 for linear agents). For linear agents, a statistically significant increase was found between 4-8 injections (-0.051±0.087) and >12 injections (0.16±0.125). No neurological symptoms were recorded in patients with signal changes. Multiple injections of linear gadolinium-based contrast agents lead to a signal increase of the dentate nucleus in children. Signal intensity increases depend on the number of injections of linear contrast agents.

Synthesis and Assessment of Peptide Gd-DOTA Conjugates Targeting Extradomain B Fibronectin for Magnetic Resonance Molecular Imaging of Prostate Cancer.

Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand-receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl3. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd-DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd-DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.

Repeated intravenous administration of gadobutrol does not lead to increased signal intensity on unenhanced T1-weighted images-a voxel-based whole brain analysis.

To identify a possible association between repeated intravenous administration of gadobutrol and increased signal intensity in the grey and white matter using voxel-based whole-brain analysis. In this retrospective single-centre study, 217 patients with a clinically isolated syndrome underwent baseline brain magnetic resonance imaging and at least one annual follow-up examination with intravenous administration of 0.1mmol/kg body weight of gadobutrol. Using the "Diffeomorphic Anatomical Registration using Exponentiated Lie algebra" (DARTEL) normalisation process, tissue templates for grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were calculated, as were GM-CSF and WM-CSF ratios. Voxel-based whole-brain analysis was used to calculate the signal intensity for each voxel in each data set. Paired t-test was applied to test differences to baseline MRI for significance. Voxel-based whole-brain analysis demonstrated no significant changes in signal intensity of grey and white matter after up to five gadobutrol administrations. There was no significant change in GM-CSF and grey WM-CSF ratios. Voxel-based whole-brain analysis did not demonstrate increased signal intensity of GM and WM on unenhanced T1-weighted images after repeated gadobutrol administration. The molecular structure of gadolinium-based contrast agent preparations may be an essential factor causing SI increase on unenhanced T1-weighted images. • Repeated administration of gadobutrol does not lead to increased signal intensity. • Voxel-based whole-brain analysis allows assessment of subtle changes in signal intensity. • Macrocyclic contrast agents in a proven dosage are safe.

Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America.

Numerous recent articles have reported brain gadolinium deposition when using linear but not macrocyclic gadolinium-based contrast agents (GBCAs). To determine the current landscape of gadolinium use among pediatric institutions and the knowledge base of radiologists and referring providers with regard to GBCAs and brain gadolinium deposition. We e-mailed voluntary closed surveys to 5,390 physicians in various pediatric professional societies between January 2016 and March 2016. We used chi-square and Fisher exact tests to compare response distributions among specialties. We found that 80% of surveyed pediatric hospitals use macrocyclic contrast agents. In the last year, 58% switched their agent, most commonly to gadoterate meglumine, with the most common reason being brain gadolinium deposition. Furthermore, surveys indicated that 23% of hospitals are considering switching, and, of these, 83% would switch to gadoterate meglumine; the most common reasons were brain gadolinium deposition and safety. Radiologists were more aware of brain gadolinium deposition than non-radiologist physicians (87% vs. 26%; P<0.0001). Radiologists and referring providers expressed similar levels of concern (95% and 89%). Twelve percent of radiologists and 2% of referring providers reported patients asking about brain gadolinium deposition. Radiologists were significantly more comfortable addressing patient inquiries than referring pediatric physicians (48% vs. 6%; P<0.0001). The number of MRIs requested by referring pediatric physicians correlated with their knowledge of brain gadolinium deposition, contrast agent used by their hospital, and comfort discussing brain gadolinium deposition with patients (P<0.0001). Since the discovery of brain gadolinium deposition, many pediatric hospitals have switched to or plan to switch to a more stable macrocyclic MR contrast agent, most commonly gadoterate meglumine. Despite this, there is need for substantial further education of radiologists and referring pediatric providers regarding GBCAs and brain gadolinium deposition.

Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study.

Recently, several studies reported increased signal intensity (SI) in the dentate nucleus (DN) after repeated application of gadolinium-based contrast agents (GBCAs), suggesting a deposition of gadolinium in this location. Patients with relapsing–remitting multiple sclerosis (RRMS) frequently show increased permeability of the blood–brain barrier as part of the inflammatory process in the brain parenchyma, which theoretically might increase the risk of gadolinium deposition. In this retrospective study, we investigated a possible increasing SI in the DN after repeated administrations of the macrocyclic contrast agent gadoterate meglumine.Forty-one RRMS patients (33 women, mean age 38 years) with at least 6 prior gadolinium-enhanced examinations (single dose gadoterate meglumine) were identified. A total of 279 unenhanced T1-weighted examinations were analyzed.SI ratio differences did not differ between the first and last MRI examination, neither for the DN-to-pons ratio (P = 0.594) nor for the DN-to-cerebellum ratio (P = 0.847). There was no correlation between the mean DN-to-pons, or between the mean DN-to-cerebellum SI ratio and the number of MRI examinations (P = 0.848 and 0.891), disease duration (P = 0.676 and 0.985), and expanded disability status scale (EDSS) (P = 0.639 and 0.945).We found no signal increases in the DN after a minimum of 6 injections of the macrocyclic GBCA gadoterate meglumine in RRMS patients. This warrants further investigations in regard to the true pathophysiologic basis of intracerebral gadolinium deposition.

Erratum to: Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5years.

To investigate if application of macrocyclic gadolinium-based contrast agents in volunteers is associated with neuronal deposition detected by magnetic resonance imaging in a 5-year longitudinal survey. Three hundred eighty-seven volunteers who participated in a population-based study were enrolled. Subjects underwent plain T1-weighted brain MRI at baseline and 5 years later with identical sequence parameters. At baseline, 271 participants additionally received intravenous injection of the macrocyclic contrast agent gadobutrol (1.5 mmol/kg). A control group including 116 subjects received no contrast agent. Relative signal intensities of thalamus, pallidum, pons and dentate nucleus were compared at baseline and follow-up. No difference in relative signal intensities was observed between contrast group (thalamus, p = 0.865; pallidum, p = 0.263; pons, p = 0.533; dentate nucleus, p = 0.396) and control group (thalamus, p = 0.683; pallidum; p = 0.970; pons, p = 0.773; dentate nucleus, p = 0.232) at both times. Comparison between both groups revealed no significant differences in relative signal intensities (thalamus, p = 0.413; pallidum, p = 0.653; pons, p = 0.460; dentate nucleus, p = 0.751). The study showed no significant change in globus pallidus-to-thalamus or dentate nucleus-to-pons ratios. Five years after administration of a 1.5-fold dose gadobutrol to normal subjects, signal intensity of thalamus, pallidum, pons and dentate nucleus did not differ from participants who had not received gadobutrol. • Gadobutrol does not lead to neuronal signal alterations after 5 years. • Neuronal deposition of macrocyclic contrast agent could not be confirmed. • Macrocyclic contrast agents in a proven dosage are safe.

Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5years.

To investigate if application of macrocyclic gadolinium-based contrast agents in volunteers is associated with neuronal deposition detected by magnetic resonance imaging in a 5-year longitudinal survey. Three hundred eighty-seven volunteers who participated in a population-based study were enrolled. Subjects underwent plain T1-weighted brain MRI at baseline and 5years later with identical sequence parameters. At baseline, 271 participants additionally received intravenous injection of the macrocyclic contrast agent gadobutrol (0.15mmol/kg). A control group including 116 subjects received no contrast agent. Relative signal intensities of thalamus, pallidum, pons and dentate nucleus were compared at baseline and follow-up. No difference in relative signal intensities was observed between contrast group (thalamus, p = 0.865; pallidum, p = 0.263; pons, p = 0.533; dentate nucleus, p = 0.396) and control group (thalamus, p = 0.683; pallidum; p = 0.970; pons, p = 0.773; dentate nucleus, p = 0.232) at both times. Comparison between both groups revealed no significant differences in relative signal intensities (thalamus, p = 0.413; pallidum, p = 0.653; pons, p = 0.460; dentate nucleus, p = 0.751). The study showed no significant change in globus pallidus-to-thalamus or dentate nucleus-to-pons ratios. Five years after administration of a 1.5-fold dose gadobutrol to normal subjects, signal intensity of thalamus, pallidum, pons and dentate nucleus did not differ from participants who had not received gadobutrol. • Gadobutrol does not lead to neuronal signal alterations after 5years. • Neuronal deposition of macrocyclic contrast agent could not be confirmed. • Macrocyclic contrast agents in a proven dosage are safe.

Safety and efficacy of gadoteric acid in pediatric magnetic resonance imaging: overview of clinical trials and post-marketing studies.

Gadoteric acid is a paramagnetic gadolinium macrocyclic contrast agent approved for use in MRI of cerebral and spinal lesions and for body imaging. To investigate the safety and efficacy of gadoteric acid in children by extensively reviewing clinical and post-marketing observational studies. Data were collected from 3,810 children (ages 3 days to 17 years) investigated in seven clinical trials of central nervous system (CNS) imaging (n = 141) and six post-marketing observational studies of CNS, musculoskeletal and whole-body MR imaging (n = 3,669). Of these, 3,569 children were 2-17 years of age and 241 were younger than 2 years. Gadoteric acid was generally administered at a dose of 0.1 mmol/kg. We evaluated image quality, lesion detection and border delineation, and the safety of gadoteric acid. We also reviewed post-marketing pharmacovigilance experience. Consistent with findings in adults, gadoteric acid was effective in children for improving image quality compared with T1-W unenhanced sequences, providing diagnostic improvement, and often influencing the therapeutic approach, resulting in treatment modifications. In studies assessing neurological tumors, gadoteric acid improved border delineation, internal morphology and contrast enhancement compared to unenhanced MR imaging. Gadoteric acid has a well-established safety profile. Among all studies, a total of 10 children experienced 20 adverse events, 7 of which were thought to be related to gadoteric acid. No serious adverse events were reported in any study. Post-marketing pharmacovigilance experience did not find any specific safety concern. Gadoteric acid was associated with improved lesion detection and delineation and is an effective and well-tolerated contrast agent for use in children.

Safety and Efficacy of Gadobutrol for Contrast-enhanced Magnetic Resonance Imaging of the Central Nervous System: Results from a Multicenter, Double-blind, Randomized, Comparator Study.

PURPOSEContrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood–brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight.MATERIALS AND METHODSProspective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology.RESULTSOf the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging (P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%).CONCLUSIONGadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity.