Gadolinium-based Magnetic Resonance Contrast Agent Research Articles

Pharmacoeconomic Evaluation of Using One-Molar Gadolinium-Based Magnetic Resonance Contrast Agent Compared to Half-Molar Agents for the Diagnosis of Multiple Sclerosis

Objective: to conduct a comparative assessment of the pharmacoeconomic advantages of using gadobutrol in comparison with half-molar (0.5 M) gadolinium chelates for the diagnosis of multiple sclerosis (MS). Material and methods . A calculator was developed in Microsoft Excel, in which the number of exacerbations of multiple sclerosis was obtained when using one-molar (1.0 M) gadolinium-based contrast agents (GBCAs) and 0.5 M gadolinium chelates, and pharmacoeconomical results were analyzed by conducting a cost analysis and a budget impact analysis. The analysis took into account only direct medical costs (research costs (administering of GBCAs) and hospitalization costs due to exacerbations) funded under the mandatory health insurance system. The results have been calculated for a cohort of 1.000 patients. Results. The analysis of pharmacoeconomic effectiveness showed that magnetic resonance studies of the central nervous system using gadobutrol were characterized by a reduction in the number of MS exacerbations by 70 cases. In the cost analysis the use of gadobutrol in both patients less than 75 kg (7.5 ml administered volume) and more than 75 kg (15 ml administered volume) demonstrated a reduction in total costs compared to 0.5 M gadolinium chelates (gadodiamide, gadoteric acid, and gadoteridol). Budget impact analysis showed that the transfer of 1.000 patients with studies using 0.5 M GBCAs on the gadobutrol due to the reduction in the incidence of MS exacerbations leads to budgetary savings in the group of patients under 75 kg from 4.264.610 to 6.565.827 RUB, and in patients more than 75 kg from 2.267.767 to 6.870.201 RUB. Conclusion. As a result of pharmacoeconomical modeling, it was found that the use of gadobutrol for central nervous system studies for the diagnosis of MS in comparison with using 0.5 GBCAs can reduce the number of MS exacerbations and lead to money savings.

Localized Blood–Brain Barrier Opening in Ovine Model Using Image-Guided Transcranial Focused Ultrasound

Transcranial application of focused ultrasound (FUS) combined with vascular introduction of microbubble contrast agents (MBs) has emerged as a non-invasive technique that can temporarily create a localized opening in the blood–brain barrier (BBB). Under image-guidance, we administered FUS to sheep brain after intravenous injection of microbubbles. BBB opening was confirmed by performing dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to detect the extravasated gadolinium-based magnetic resonance contrast agents. Through pharmacokinetic analysis as well as independent component analysis of the DCE-MRI data, we observed localized enhancement in BBB permeability at the area that subjected to acoustic pressure of 0.48 MPa (mechanical index = 0.96). On the other hand, application of a higher pressure at 0.58 MPa resulted in localized, minor cerebral hemorrhage. No animals exhibited abnormal behavior during the post-FUS survival periods up to 2 mo. Our data suggest that monitoring for excessive BBB disruption is important for safe translation of the method to humans.

Preventive Effect of Changing Contrast Media in Patients With A Prior Mild Immediate Hypersensitivity Reaction to Gadolinium-Based Contrast Agent.

Currently, the prevention of recurrent immediate hypersensitivity reactions (HSRs) to contrast media (CM) requests premedication and changing the culprit contrast agent. However, strategies for the prevention of immediate HSRs to gadolinium-based magnetic resonance contrast agents (GBCAs) have not yet been established. This study aimed to evaluate the effectiveness of changing the contrast agent and single-dose premedication for HSR recurrence prevention in patients with a history of mild immediate HSR to GBCA. The outcomes of patients with mild immediate HSR to GBCA who subsequently underwent enhanced magnetic resonance imaging between October 2012 and July 2017 were analyzed. The institutional CM monitoring system was retrospectively reviewed, and data on the application of premedication and choice of CM were obtained. Gadolinium-based magnetic resonance contrast agents were classified into 3 classes according to their molecular structure (macrocyclic ionic, macrocyclic nonionic, and linear ionic). Intravenous chlorpheniramine 4 mg, 30 minutes before the GBCA administration, or intravenous methylprednisolone sodium succinate 40 mg plus chlorpheniramine 4 mg, 1 hour before the GBCA administration, was administrated as premedication regimen. Recurrence rates of immediate HSR were compared according to prevention strategies. A total of 185 patients with a history of mild immediate HSR to GBCA were re-exposed to GBCA 397 times during the study period. The overall recurrence rate was 19.6% (78/397). Changing the culprit GBCA significantly reduced the recurrence rate, compared with reusing the culprit GBCA (6.9%, 9/130 and 25.8%, 69/267; P < 0.001). The recurrence rate was lowest when the GBCA was changed to a different molecular structure class from the culprit agent, followed by changing to CM with the same molecular structure and reusing the culprit GBCA (6.2%, 7/113 vs 11.8%, 2/17 vs 25.8%, 69/267; P < 0.001 with χ test for trend). Single-dose premedication demonstrated no significant prophylactic effect on recurrence (20.4%, 17/98 vs 17.3%, 61/299 with and without premedication, respectively; P = 0.509). Premedication in addition to changing CM also showed no additional prophylactic effect (7.2%, 7/97 and 6.1%, 2/33, respectively; P = 0.821). Changing the CM from the culprit agent could reduce the chance of HSR recurrence in patients with prior mild immediate HSR to GBCA, especially when the CM was changed to one of a different molecular structure class. However, single-dose premedication administration did not show significant HSR recurrence rate difference.

Biodegradable and Renal-Clearable Hollow Porous Iron Oxide Nanoboxes for in Vivo Imaging

For in vivo imaging, it is important that imaging agents could be harmlessly eliminated from the body after performing their functions. Gadolinium-based magnetic resonance contrast agents have been...

Magnetic Resonance Imaging Using Gadolinium-Based Contrast Agents

The purpose of this article was to review the basic properties of available gadolinium-based magnetic resonance contrast agents, discuss their fundamental differences, and explore common and evolving applications of gadolinium-based magnetic resonance contrast throughout the body excluding the central nervous system. A more specific aim of this article was to explore novel uses of these gadolinium-based contrast agents and applications where a particular agent has been demonstrated to behave differently or be better suited for certain applications than the other contrast agents in this class.

In vivo magnetic resonance imaging of mice liver tumors using a new gadolinium-based contrast agent

We compared the enhancement effect between a newly synthesized tissue-specific contrast agent, [Gd-DOTA-FPβG], and a commercially available agent, [Gd(DOTA)]−, in a murine model of liver tumor using a clinical magnetic resonance imaging scanner. The colon cancer cell lines with and without β-glucuronidase (βG) expression were implanted into the liver of mice. Self-synthesized gadolinium-based magnetic resonance contrast agent, [Gd(DOTA-FPβG)], was administered to measure enhancement on magnetic resonance images using a commercially available agent, [Gd(DOTA)]−, as control in a clinical 3.0 tesla (T) magnetic resonance scanner. In vivo fluorescence imaging and histopathology of the liver were also performed to compare and correlate with the magnetic resonance studies. The in vivo fluorescence imaging failed to depict a sufficiently intense signal for liver or liver tumor of mice without exposure of the liver following an incision on the abdominal wall. The tissue-specific magnetic resonance agent, [Gd(DOTA-FPβG)], caused significantly stronger enhancement in tumors expressing βG (CT26/mβG-eB7) than in tumors not expressing βG (CT26) (p < 0.05). In the magnetic resonance imaging studies using control agent [Gd(DOTA)]−, the tumors with and without βG expression depicted no significant difference in enhancement on the T1-weighted images. The [Gd(DOTA-FPβG)] also provided significantly more contrast uptake in the CT26/mβG-eB7 tumor than in the normal liver parenchyma, whereas the [Gd(DOTA)]− did not. This study confirms that better contrast enhancement can be readily detected in vivo by the use of a tissue-specific magnetic resonance contrast agent to target tumor cells with specific biomarkers in a clinical magnetic resonance imaging scanner.

NFκB activation and stimulation of chemokine production in normal human macrophages by the gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis

ObjectiveNephrogenic systemic fibrosis (NSF) is a generalised fibrotic disorder occurring in certain individuals with renal insufficiency exposed to gadolinium-based contrast agents (GdBCA) for MRI. Histopathological examination of affected tissues shows...

Identification and characterization of gadolinium(iii) complexes in biological tissue extracts

The gadolinium species present in a rat kidney following intravenous administration of a gadolinium-based magnetic resonance contrast agent (Optimark™, Gadoversetamide injection) to a rat was examined in the present study. The major gadolinium species in the supernatant of the rat kidney tissue extracts was determined by reversed-phase liquid chromatography with online inductively coupled plasma optical emission spectrometry (HPLC-ICP-OES). The identity of the compound was established by liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) detection. The principal gadolinium(III) complex in a rat kidney tissue extract was identified as Gd-DTPA-BMEA 24 Hrs and 7 days after a single intravenous injection of Optimark™ (gadoversetamide; Gd-DTPA-BMEA) at a dose of 5 mmol Gd/kg body weight. The study demonstrated for the first time the feasibility of the use of two complementary techniques, HPLC-ICP-OES and HPLC-ESI-MS to study the in vivo behavior of gadolinium-based magnetic resonance contrast media.

Cell-Penetrating Peptides and Peptide Nucleic Acid-Coupled MRI Contrast Agents: Evaluation of Cellular Delivery and Target Binding

Molecular imaging of cells and cellular processes can be achieved by tagging intracellular targets such as receptors, enzymes, or mRNA. Seeking to visualize the presence of specific mRNAs by magnetic resonance (MR) imaging, we coupled peptide nucleic acids (PNA) with gadolinium-based MR contrast agents using cell-penetrating peptides for intracellular delivery. Antisense to mRNA of DsRed2 protein was used as proof of principle. The conjugates were produced by continuous solid-phase synthesis followed by chelation with gadolinium. Their cellular uptake was confirmed by fluorescence microscopy and spectroscopy as well as by MR imaging of labeled cells. The cell-penetrating peptide D-Tat(57-49) was selected over two other derivatives of HIV-1 Tat peptide, based on its superior intracellular delivery of the gadolinium-based contrast agents. Further improved delivery of conjugates was achieved upon coupling peptide nucleic acids (antisense to mRNA of DsRed2 protein and nonsense with no natural counterpart). Significant enhancement in MR contrast was obtained in cells labeled with concentrations as low as 2.5 μM of these agents. Specific binding of the targeting PNA containing conjugate to its complementary oligonucleotide sequence was proven by in vitro cell-free assay. In contrast, a lack of specific enrichment was observed in transgenic cells containing the target due to nonspecific vesicular entrapment of contrast agents. Preliminary biodistribution studies showed conjugate-related fluorescence in several organs, especially the liver and bladder, indicating high mobility of the agent in spite of its high molecular weight. No conjugate related toxicity was observed. These results are encouraging, as they warrant further molecular optimization and consecutive specificity studies in vivo of this new generation of contrast agents.

Imaging in Intestinal Ischemic Disorders

Intestinal ischemia and infarction are a heterogeneous group of diseases that have as their unifying theme hypoxia of the small bowel and/or colon. The incidence of bowel ischemia is increasing for a number of reasons: the aging of the population, the ability of intensive care units to salvage critically ill patients, and heightened clinical awareness of these disorders. Improvements in diagnostic imaging techniques have contributed greatly to the earlier diagnosis of intestinal ischemia, which can have a positive influence on patient outcomes. In this review, advances in multidetector computerized tomography, magnetic resonance, and ultrasound in the detection of intestinal ischemia are highlighted and placed in the context of expeditious patient management.

The Impact of NSF on the Care of Patients With Kidney Disease

The association of nephrogenic systemic fibrosis (NSF) with the use of gadolinium-based magnetic resonance contrast agents (GBMCAs) has greatly affected the care of patients with kidney disease. Nephrogenic systemic fibrosis has been reported in patients with end-stage renal disease, chronic kidney disease (CKD) and acute kidney injury. The majority of cases have occurred in patients with end-stage renal disease, but cases of NSF have been reported in CKD patients with glomerular filtration rates less than 30 mL/min/1.73 m(2). Odds ratios have ranged between 8.97 and 32.5 among patients exposed to GBMCAs. Given the significant morbidity, disability, and mortality associated with NSF, it is imperative to properly and preemptively identify those patients at risk. Patients with end-stage renal disease seem to be at highest risk, particularly those maintained on peritoneal dialysis (PD). Although there are no data to support a role for hemodialysis in reducing the risk for NSF after the administration of GBMCAs, hemodialysis is recommended within 2 to 3 hours. Patients maintained on PD and those with CKD present a challenge, as they do not typically have vascular access for hemodialysis, yet the clearance of GBMCAs is very low, and it may be prudent to consider hemodialysis especially for PD patients. Gadolinium-based magnetic resonance contrast agents are removed by dialysis, with estimates that about 99% of a dose is removed after 3 to 4 sessions of hemodialysis. The elimination half-life averaged 9 hours in patients with stage 4 CKD (glomerular filtration rate <30 mL/min/1.73 m(2)) compared with 1.5 hours in those with normal glomerular filtration rates. This prolonged elimination and longer exposure may be important factors in predisposing to NSF.

Impact on Hospital Policy: Yale Experience

To limit patients who may be at risk for nephrogenic systemic fibrosis from exposure to gadolinium-based magnetic resonance contrast agents, new policies and procedures have been implemented at Yale-New Haven Hospital. These changes include screening patients for low estimated glomerular filtration rates and risk factors for chronic kidney disease, giving increased attention to the types and doses of contrast agent administered, agreement on alternative imaging algorithms, and education at all levels of the medical community. The rationale for these changes is discussed.

Nephrogenic Fibrosing Dermopathy/Nephrogenic Systemic Fibrosis (NFD/NSF) and Gadolinium-Based Magnetic Resonance Contrast Agents (GBMCAs): A Literature Review

Health Canada and the Food and Drug Administration (FDA) in the United States have recently issued warnings pertaining to the use of gadolinium-based magnetic resonance contrast agents in patients with renal insufficiency. A strong temporal relationship between the administration of gadolinium agents and the development of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis in this patient cohort has been established. This study presents a review of the literature, description of the disease, and discussion of possible contributing co-factors to its development. Best practice recommendations are provided for medical radiation technologists for management of patients with renal insufficiencies that may need to undergo magnetic resonance imaging with a gadolinium-based magnetic resonance contrast agent.

Preparation, characterization and application of an albumin-linked, gadolinium-based magnetic resonance contrast agent

Preparation, characterization and application of an albumin-linked, gadolinium-based magnetic resonance contrast agent

Bile-tagged 3d magnetic resonance colonography after exclusive intravenous administration of gadobenate dimeglumine, a contrast agent with partial hepatobiliary excretion.

Imaging of the colon is an important diagnostic procedure. Endoscopic colonoscopy and x-ray barium enemas are currently the standard diagnostic procedures. Magnetic resonance (MR) and computed tomographic colonography have been recently introduced with true three-dimensional (3D) cross-sectional imaging. Up to now, all imaging techniques have required the use of oral and/or aboral contrast agents for luminal enhancement and commonly, a relaxation medication (glucagon or N-butylscopolamine). While performing several phase I, II, and III studies with a new partially hepatobiliary excreted gadolinium-based MR contrast agent, we noted substantial intraluminal enhancement within the colon and investigated its potential for imaging. Three-dimensional MR angiographic techniques enable imaging of large volumes. We have used these sequences to detect contrast enhancement within the hepatobiliary and gastrointestinal systems. A 3D volume of 40 x 32 x 12 cm with 42 images was acquired under breath-hold. Six volunteers were studied according to the protocol. No bowel preparation was performed and no medication given. Subsequent follow-ups of the abdomen were performed at 1, 12, 24, 36, 48, 70, and 105 hours postinjection. Gadobenate dimeglumine at 0.1 mmol/kg body weight was given intravenously. Images were assessed quantitatively and by blinded reader analysis. Intense intraluminal contrast enhancement within the colon was seen within 24 hours in all subjects. The homogeneous enhancement was of sufficient intensity to enable 3D visualization and virtual endoscopy. The optimal time window for imaging was determined to be 16 to 50 hours postinjection. We report for the first time the feasibility of exclusively bile-tagged MR colonography with the use of only an intravenous MR contrast that exhibits partial hepatobiliary excretion. This new diagnostic procedure will enable not only morphological assessment of the colon but also functional and pathophysiological studies on the transport kinetics of bile and stool without any preparation of the patient.