Assessment of first-time and repeated acute adverse reactions to gadolinium-based contrast agents in MRI: A retrospective study.

PURPOSE: To identify gadolinium-based contrast agents (GBCAs)-related and patient-related risk factors for acute adverse reactions (AARs), and to examine the incidence and severity of repeated AARs. METHODS: This study retrospectively evaluated all intravenous GBCA injections in MRI studies at a single institution from January 2012 to September 2019. First-time AARs in patients without a past history of AARs and risk factors were assessed using multivariable regression models with generalized estimating equations. For patients with a past history of AAR(s), we evaluated the incidence of repeated AARs using the Fisher's exact test, as well as the severity of these repeated AARs. RESULTS: First-time AARs occurred in 129 of 41,827 GBCA injections (0.31 %; 0.70 % of 18,431 patients). With gadoterate meglumine as the reference, the odds ratio (OR) for allergic-like reactions to three GBCAs ranged from 3.27 to 8.03 (p = 0.012 to <0.001). For chemotoxic reactions, the OR was 3.75 (p = 0.001) for gadoteridol. Outpatients had a lower OR for chemotoxic reactions, while higher ORs were observed in head/neck and breast MRI (p < 0.05). The OR for age was 0.99 (p < 0.05). Patients with a past history of AAR(s) had a 3.6 % incidence of mild repeated AARs for all GBCA, significantly higher than the 0.31 % in first-time AARs (p < 0.001). No effectiveness was found for steroid premedication. CONCLUSION: The occurrence of first-time AARs was related to the GBCA used and other factors. The incidence of repeated AARs was higher than first-time AARs, though all were mild in severity.

Assessment of immediate and non-immediate hypersensitivity contrast reactions by skin tests and provocation tests: A review.

INTRODUCTION: Allergic and nonallergic hypersensitivity reactions to iodinated contrast media (ICM) and gadolinium-based contrast media are classified as immediate or non-immediate hypersensitivity reactions (IHR and NIHR), respectively. Skin tests and provocation tests are recommended for the evaluation of hypersensitivity reactions to contrast agents; however provocations are not common in clinical practice. METHODS: A MEDLINE search was conducted to investigate studies comprising both skin tests and provocation tests that evaluated hypersensitivity reactions to ICM. RESULTS: Nineteen studies were identified that reported on skin tests, followed by provocations. In the case of IHR to ICM, 65/69 (94%) patients with a positive skin test for the culprit media tolerated a challenge with a skin-test-negative alternative ICM. In IHR to ICM with a negative skin test for the culprit media, provocations were positive in 3.2%-9.1% patients. In the case of a NIHR to ICM with a positive skin test, provocation with a skin-test-negative agent was tolerated in 75/105 (71%) of cases. In NIHR with a negative skin test for the culprit agent, re-exposure to the culprit or an alternative was positive in 0%-34.6% patients. Provocations with the same ICM in skin test positive patients with IHR or NIHR were positive for a majority of the patients, although such provocation tests were rarely performed. Data on hypersensitivity reactions, skin tests and provocations with gadolinium-based contrast media were limited; however, they exhibited a pattern similar to that observed in ICM. CONCLUSION: In both ICM and gadolinium-based contrast media, the risk of an immediate repeat reaction is low when skin tests are negative. In contrast, a provocation with a skin-test-positive contrast medium showed a high risk of an immediate repeat hypersensitivity reaction. Therefore, a thorough medical history is necessary, followed by skin tests. A provocation is recommended, for diagnostic work-up, when the diagnosis is uncertain.

Assessment of Gadobutrol Safety in Combination with Ionizing Radiation Using a Preclinical MRI-Guided Radiotherapy Model.

MR-linac technology enhances the precision of therapeutic radiation by clarifying the tumor-normal tissue interface and provides the potential for adaptive treatment planning. Accurate delineation of tumors on diagnostic magnetic resonance imaging (MRI) frequently requires gadolinium-based contrast agents (GBCAs). Despite generally being considered safe, previous literature suggests that GBCAs are capable of contrast-induced acute kidney injury (AKI). It is unclear if the risk for AKI is enhanced when GBCAs are administered concurrently with ionizing radiotherapy. During irradiation, gadolinium may be liberated from its chelator which may induce AKI. The goal of this work was to determine if radiation combined with GBCAs increased the incidence of AKI. Using a preclinical MRI-guided irradiation system, where MRI acquisitions and radiation delivery are performed in rapid succession, tumor-bearing mice with normal kidney function were injected with GBCA and treated with 2, 8 or 18 Gy irradiation. Renal function was assessed on days three and seven postirradiation to assess for AKI. No clinically relevant changes in blood urea nitrogen and creatinine were observed in any combination of GBCA and radiation dose. From these data, we conclude that GBCA in combination with radiation does not increase the risk for AKI in mice. Additional investigation of multiple doses of GBCA administered concurrently with irradiation is warranted to evaluate the risk of chronic kidney injury.

Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration.

BACKGROUND AND PURPOSE: Nephrogenic systemic fibrosis following administration of intravenous gadobenate during MR imaging is rare. This study aimed to analyze any nephrogenic systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate. MATERIALS AND METHODS: In this retrospective study with a prospective skin biopsy phase, patients with estimated glomerular filtration rates of <60 mL/min/1.73 m2 undergoing contrast-enhanced MR imaging from July 2007 through June 2014 were screened for nephrogenic systemic fibrosis using a questionnaire. This was highly sensitive but not specific and reliably excluded nephrogenic systemic fibrosis if responses to at least 6 of the 8 questions were negative. If no nephrogenic systemic fibrosis was detected, a skin biopsy was requested. RESULTS: Of 2914 patients who met these criteria, 1988 were excluded for various reasons. Of the remaining 926 patients, 860 were screened negative for nephrogenic systemic fibrosis. Of these, 17 (2%) had estimated glomerular filtration rates of <15 mL/min/1.73 m2, 51 (6%) had levels of 15 < 30 mL/min/1.73 m2, 234 (27%) had levels of 30 < 45 mL/min/1.73 m2, and 534 (62%) had levels of 45 < 60 mL/min/1.73 m2. Of the 66 who were not cleared of nephrogenic systemic fibrosis by the questionnaire, 6 patients were evaluated by a dermatologist and confirmed not to have nephrogenic systemic fibrosis (no biopsy required). CONCLUSIONS: A diagnosis of nephrogenic systemic fibrosis was excluded in 860 patients with impaired renal function who were followed up and received gadobenate during MR imaging. In 14 such patients who underwent at least 1 gadobenate-enhanced MR imaging examination and did not have nephrogenic systemic fibrosis, gadolinium levels in the skin were exceedingly low.

New OFSEP recommendations for MRI assessment of multiple sclerosis patients: Special consideration for gadolinium deposition and frequent acquisitions.

PURPOSE: New multiple sclerosis (MS) disease-modifying therapies (DMTs), which exert beneficial effects through prevention of relapse, limitation of disability progression, and improvement of patients' quality of life, have recently emerged. Nonetheless, these DMTs are not without associated complications (severe adverse events like. progressive multifocal leukoencephalopathy). Patient follow-up requires regular clinical evaluations and close monitoring with magnetic resonance imaging (MRI). Detection of new T2 lesions and potential brain atrophy measurements contribute to the evaluation of treatment effectiveness. Current MRI protocols for MS recommend the acquisition of an annual gadolinium (Gd) enhanced MRI, resulting in administration of high volume of contrast agents over time and Gd accumulation in the brain. METHODS: A consensus report was established by neuroradiologists and neurologists from the French Observatory of MS, which aimed at reducing the number of Gd injections required during MS patient follow-up. RECOMMENDATIONS: The French Observatory of MS recommends the use of macrocyclic Gd enhancement at time of diagnosis, when a new DMT is introduced, at 6-month re-baseline, and when previous scans are unavailable for comparison. Gd administration can be performed as an option in case of relapse or suspicion of intercurrent disease such as progressive multifocal leukoencephalopathy. Other follow-up MRIs do not require contrast enhancement, provided current and previous MRI acquisitions follow the same standardized protocol including 3D FLAIR sequences.

Gadolinium Deposition Disease: A New Risk Management Threat.

Gadolinium-based contrast agents (GBCAs) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30% of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety profile and attendant medicolegal liability associated with GBCAs changed in 2016 with the description of gadolinium deposition disease (GDD). Despite being unproven scientifically, a groundswell of GDD-related litigation and personal injury advertising targeting potential GDD patients has occurred. In this article, we describe what GDD is, why GDD has created medicolegal risk, and how this risk might be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the period of purported GDD development. As such, based on the currently available data, the authors recommend the preferential use of gadoteridol as the default GBCA for MRI imaging.

Dechelation (Transmetalation): Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan).

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

10 Years of Nephrogenic Systemic Fibrosis: A Comprehensive Analysis of Nephrogenic Systemic Fibrosis Reports Received by a Pharmaceutical Company from 2006 to 2016.

OBJECTIVES: The aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016. MATERIALS AND METHODS: A total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports. RESULTS: For all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting. CONCLUSIONS: Year of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.

Retention of gadolinium compounds used in magnetic resonance imaging: a critical review and the recommendations of regulatory agencies. / Retención de compuestos de gadolinio usados en resonancia magnética: revisión crítica y recomendaciones de las agencias regulatorias.

The Spanish Agency for Drugs and Healthcare Products (AEMPS), based on the recommendations of the European Committee for Risk Assessment in Pharmacovigilance, established on 13 March 2017 that linear gadolinium-based MR contrast media, such as MultiHance, Omniscan, Magnevist (currently not marketed) and Optimark (no longer marketed in Spain), the clinical benefits do not outweigh the potential risks derived from their use. AEMPS recommends to suspend its marketing for general use based on the retention of these compounds in the brain. On the other hand, the AEMPS justifies the maintenance of Primovist and MultiHance for liver studies, and Magnevist of intra-articular administration (not commercialized in Spain), and justified the almost exclusive use of macrocyclic structure contrasts (Gadovist, ProHance and Dotarem). However, this retention is known to be different for each of the contrast media. All existing gadolinium contrasts agents have a distribution phase with tissue retention, due to a very slow exchange, in the interstitium of bone, skin, kidney, brain and other organs. The existence of histological effects or clinical symptoms associated with the accumulation of these trace amounts of gadolinium has not been demonstrated. The major toxicological concern with these contrast agents is related to nephrogenic systemic fibrosis (NSF). Since the safety profiles are mainly related to the interstitial retention space in the tissues, it does not seem justified to actually exclude contrast media that do not have cases related to the NSF. Based on all of this, we disagree with the latest AEMPS recommendation suggesting the marketing stoppage of linear agents without considering the individual retention profiles. This recommendation is not based neither on the data nor existing knowledge about the retention, relaxivity and clinical efficiency of the Gd compounds. It is therefore necessary to carry out prospective studies on the histological and clinical relevance of these organic Gd deposits.

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents.

For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

Gadolinium-based contrast agents: A comprehensive risk assessment.

Gadolinium-based contrast agents (GBCAs) have been used in magnetic resonance imaging (MRI) since the 1980s and are now administered in up to 35% of all MRI examinations. While GBCAs were initially felt to carry minimal risk, the subsequent identification of GBCAs as the key etiologic factor in the development of nephrogenic systemic fibrosis (NSF) has raised concerns about the broader health impacts of gadolinium exposure. Clinicians, radiologists, and patients should be aware of the most up-to-date data pertaining to the risks of GBCA administration. Specific issues covered in this review article include immediate adverse reactions; pregnancy and lactation; and gadolinium deposition and toxicity, with a special focus on NSF. Practice recommendations based on the presented data, as well as current professional society guidelines, are provided for each section. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. MAGN. RESON. IMAGING 2017;46:338-353.

In vivo quantitative assessment of cell viability of gadolinium or iron-labeled cells using MRI and bioluminescence imaging.

In cell therapy, noninvasive monitoring of in vivo cell fate is challenging. In this study we investigated possible differences in R1, R2 or R2* relaxation rate as a measure of overall cell viability for mesenchymal stem cells labeled with Gd-liposomes (Gd-MSCs) or iron oxide nanoparticles (SPIO-MSCs). Cells were also transduced with a luciferase vector, facilitating a correlation between MRI findings and cell viability using bioluminescence imaging (BLI). Viable Gd-MSCs were clearly distinguishable from nonviable Gd-MSCs under both in vitro and in vivo conditions, clearly differing quantitatively (ΔR1 and ΔR2) as well as by visual appearance (hypo- or hyperintense contrast). Immediately post-injection,viable Gd-MSCs caused a substantially larger ΔR2 and lower ΔR1 effect compared with nonviable MSCs. With time, the ΔR1 and ΔR2 relaxation rate showed a good negative correlation with increasing cell number following proliferation. Upon injection, no substantial quantitative or visual differences between viable and nonviable SPIO-MSCs were detected. Moreover, nonviable SPIO-MSCs caused a persisting signal void in vivo, compromising the specificity of this contrast agent. In vivo persistence of SPIO particles was confirmed by histological staining. A large difference was found between SPIO- and Gd-labeled cells in the accuracy of MR relaxometry in assessing the cell viability status. Gd-liposomes provide a more accurate and specific assessment of cell viability than SPIO particles. Viable Gd cells can be differentiated from nonviable Gd cells even by visual interpretation. These findings clearly indicate Gd to be the favourable contrast agent in qualitative and quantitative evaluation of labeled cell fate in future cell therapy experiments.

[Assessment of renal function, iatrogenic hyperkalemia and acute renal dysfunction in cardiology. Contrast-induced nephropathy]. / Valoración de afección renal, disfunción renal aguda e hiperpotasemia por fármacos usados en cardiología y nefrotoxicidad por contrastes.

Renal impairment influences the prognosis of patients with cardiovascular disease and increases cardiovascular risk. Renal dysfunction is a marker of lesions in other parts of the vascular tree and detection facilitates early identification of individuals at high risk of cardiovascular events. In patients with cardiovascular disease, renal function is assessed by measuring albuminuria in a spot urine sample and by estimating the glomerular filtration rate using creatinine-derived predictive formulas or equations. We recommend the Chronic Kidney Disease Epidemiology Collaboration or the Modification of Diet in Renal Disease formulas. The Cockcroft-Gault formula is a possible alternative. The administration of drugs that block the angiotensin-renin system can, on occasion, be associated with acute renal dysfunction or hyperkalemia. We need to know when risk of these complications exists so as to provide the best possible treatment: prevention. Given the growing number of diagnostic and therapeutic procedures in the field of cardiology that use intravenous contrast media, contrast-induced nephrotoxicity represents a significant problem. We should identify the risk factors and patients at greatest risk, and prevent it from appearing.

Quantitative assessment of dermal cellularity in nephrogenic systemic fibrosis: a diagnostic aid.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) affects patients with impaired renal function who have received gadolinium-containing contrast agents (GCCAs). Increased dermal cellularity is a key diagnostic feature of NSF, however, the histologic findings can be subtle. OBJECTIVE: We sought to determine whether dermal cellularity in skin biopsy specimens from NSF cases: (1) differs significantly from that of controls; and (2) correlates with duration of the skin lesions, level of plasma creatinine, GCCA dose, or a combination of these. METHODS: Seventeen NSF skin biopsy specimens and age-, sex-, and site-matched controls were retrieved from the dermatopathology files of the Massachusetts General Hospital in Boston. Dermal cellularity was manually quantified on hematoxylin-eosin-stained sections and patient medical records were reviewed for demographic and clinical data. RESULTS: NSF cases showed a mean dermal cellularity of 70.8/high-power field (control mean: 14.4/high-power field, P < .001) and a cut-off range of 19 to 26/high-power field was established. No significant correlation was identified between dermal cellularity and demographic and clinical data. LIMITATIONS: In this retrospective analysis, duration of skin lesion was defined as the interval from most recent prior GCCA study, rather than the actual clinical onset, to time of skin biopsy, and the cumulative GCCA dose may reflect a minimum if GCCA was received at an outside institution. CONCLUSION: Enumeration of dermal cellularity on hematoxylin-eosin-stained sections can aid in the histologic diagnosis of NSF in the setting of chronic kidney disease and GCCA exposure and is independent of patient age, sex, plasma creatinine, time from last GCCA exposure, and GCCA dose.

Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases.

PURPOSE: To describe the presentation and clinical course of patients with nephrogenic systemic fibrosis (NSF) at a large acute-care hospital, to evaluate the overall incidence of NSF, and to assess the effect of a hospital-wide policy regarding gadolinium-based contrast agent (GBCA) use on NSF incidence. MATERIALS AND METHODS: A review of all cases of NSF observed at an institution from 2003 to 2008 was conducted. This HIPAA-compliant study was approved by the institutional review board. The informed consent requirement was waived. Demographics, medical history, and associated conditions were recorded. Radiologic procedures were evaluated if they were performed within 1 year prior to NSF onset. GBCA use was assessed by checking the electronic database for each procedure. The incidence of NSF was compared before and after implementation of an institutional policy designed to assess risk of NSF prior to GBCA use. RESULTS: All 33 patients with NSF (mean age, 49 years; age range, 15-78 years) had advanced renal failure (estimated glomerular filtration rate < 15 mL/min/1.73 m(2)) when the GBCA was injected. Twenty-six patients had severe chronic or end-stage renal disease, and seven had acute renal failure. The mean interval between contrast material injection and NSF onset was 29 days +/- 25 (standard deviation) (range, 4-112 days). The overall incidence of NSF was 36.5 cases per 100,000 gadolinium-enhanced magnetic resonance (MR) examinations between 2003 and 2006 and four cases per 100,000 gadolinium-enhanced MR examinations between 2007 and 2008 after screening for NSF risk was instituted (Fisher exact test, P = .001). Five patients developed NSF in the peritransplant period, and four underwent a catheter-based radiographic procedure with administration of a GBCA. CONCLUSION: Common associations of GBCA MR imaging and NSF were acute and severe chronic renal failure and liver or renal transplantation. Screening procedures performed before MR imaging to determine which patients were at risk of developing NSF appear to reduce the incidence of this complication and further support the belief that NSF is associated with GBCA administration.

Safe MR practices: self-assessment module.

The educational objectives for this self-assessment module on safe MR practices are for the participant to exercise, self-assess, and improve his or her knowledge of hazards to patients, medical personnel, and others in the MR scanner environment, and to exercise, self-assess, and improve his or her knowledge of safe practices in the operation of MR scanners.

First in vivo MRI assessment of a self-assembled metallostar compound endowed with a remarkable high field relaxivity.

{Fe[Gd(2)bpy(DTTA)(2)(H(2)O)(4)](3)}(4-) is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd(3+) centres confined into a small molecular space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r(1) = 15.8 mM(-1) s(-1) at 200 MHz, 37 degrees C, in H(2)O). Here we report the first in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H(2)O)](-) = GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg(-1) body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg(-1) BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T(1)), as calculated from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic gamma scintigraphic studies performed in Wistar rats with the metallostar compound having (153)Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

Worldwide clinical safety assessment of gadoteridol injection: an update.

Gadoteridol injection is a low molecular weight chelate complex of gadolinium (III) which is useful as a contrast agent for magnetic resonance imaging. A total of 2481 adult and pediatric subjects were studied with gadoteridol at doses from 0.025 to 0.3 mmol/kg in phase I-IIIb clinical trials in Europe and the United States. The study population had a mean age of 49 years, and included 119 patients under 18 years of age and 747 patients over 60 years of age. After 2656 administered injections of gadoteridol a total of 233 adverse events were recorded in 176 exposures, an incidence rate of 6.6 % irrespective of relationship to drug administration. The most frequently reported adverse events were nausea (1.5 %), taste perversion (0.9 %), and headache (0.6 %). All other adverse events occurred with an incidence of 0.5 % or less. This report confirms the excellent safety profile of gadoteridol in healthy subjects and patients with a variety of known or suspected pathologies.