MnDPDP for MR imaging of the liver. Results from the European phase III studies.

PURPOSE: To evaluate the diagnostic efficacy and safety of MnDPDP (Teslascan) in enhanced MR imaging. MATERIAL AND METHODS: In 2 multiple independent trials in Europe 624 patients were given MnDPDP intravenously at 5 mumol/kg b.w. Patients underwent an unenhanced MR examination comprising T1-weighted spin-echo and breath-hold gradient-echo sequences and a T2-weighted spin-echo sequence. The T1 sequences were repeated after the administration of MnDPDP. In a subgroup of 137 patients the results of the enhanced MR images were compared with the results of contrast-enhanced CT (CECT) images. RESULTS: For both types of T1-weighted sequences and when evaluating the maximum numbers of lesions seen in all imaging sequences, the total numbers of lesions seen were significantly higher in the MnDPDP-enhanced images than in the unenhanced images (p = 0.0005 and p = 0.0001, respectively). The investigators considered the enhanced images to contain "other additional information not found in the unenhanced images" in 279 (45%) of the 621 patients examined. The MnDPDP-enhanced images were also superior to the CECT images in the detection of lesions (p = 0.02). Adverse events were reported by 46 patients (7%) and infusion-associated discomfort by 26 (4%). Heart rates and systolic and diastolic blood pressures showed no clinically significant changes from baseline as a result of the administration of the contrast medium. CONCLUSION: MnDPDP was shown to be effective and safe in enhanced MR imaging of the liver.

MnDPDP for MR imaging of the liver. Results of an independent image evaluation of the European phase III studies.

PURPOSE: To evaluate the diagnostic efficacy of mangafodipir trisodium (MnDPDP, Teslascan) as a new contrast agent for MR imaging of the liver based on an independent evaluation of the MR images from the European phase III studies. MATERIAL AND METHODS: MR imaging of the liver was done at 0.5-2.0 T in 17 European centres and included T1-weighted spin-echo and gradient-echo sequences before and after administration of MnDPDP to patients at a dose of 5 mumol/kg b.w. T2-weighted images were also obtained in all cases before the i.v. injection of the agent. Images of a total of 592 patients were evaluated by 4 independent experienced radiologists who were not involved in the on-site clinical trials. RESULTS: Statistically significantly more lesions were detected (p = 0.0014) in MnDPDP-enhanced T1-weighted MR images than in unenhanced images. T1-weighted gradient-echo sequences were found to be superior to T1-weighted spin-echo sequences after injection of MnDPDP. The post-contrast images were found to be statistically significantly superior to the pre-contrast images in confidence in the presence of a lesion (p < or = 0.0001), quality of lesion delineation (p < or = 0.0001), lesion conspicuity (p < or = 0.0001) and in the confidence in the diagnosis of a lesion (p = 0.001). CONCLUSION: This independent evaluation of the European phase III trials confirmed the superiority of MnDPDP-enhanced MR images over unenhanced images for lesion detection and characterization.

MRI in children given gadodiamide injection: safety and efficacy in CNS and body indications.

The safety and efficacy of the MRI contrast medium gadodiamide injection (OMNISCAN) in children is summarised. Four open and three double-blind, multinational, multicentre comparative trials have been undertaken. Overall, 353 patients (15 days to 18 years, plus one 21 years) received gadodiamide injection, and 128 (2-18 years) received gadopentetate dimeglumine (Magnevist), intravenously at 0.1 mmol/kg body weight, to aid the identification of CNS and body lesions. Adverse events were reported in 13 (4%) patients given gadodiamide injection and 8 (6%) given gadopentetate dimeglumine; few patients reported injection-associated discomfort. The post-contrast scan gave more diagnostic information in 223 (63%) patients given gadodiamide injection (CNS and body indications). In the comparative trials, the post-contrast scan gave more diagnostic information for 91 (65%) and 82 (64%) patients given gadodiamide injection and gadopentetate dimeglumine, respectively (CNS indications only). Gadodiamide injection (0.1 mmol/kg body weight) was safe and effective in infants, children and adolescents.

Ferristene as intestinal MR contrast agent. Distribution and safety of a fast ingestion procedure with oral metoclopramide.

PURPOSE: To compare the small bowel distribution and safety of a fast ingestion procedure of ferristene to those of the standard ingestion procedure. MATERIAL AND METHODS: Sixty-four patients received 0.5 g/l ferristene in 800 ml water. Thirty-four patients of the fast ingestion group ingested ferristene with 20 mg of oral metoclopramide during the course of 30 min before MR imaging and received an i.v. injection of an antiperistaltic agent during the MR study. Thirty patients of the standard group ingested ferristene during the course of 2 h, without additional drugs. Ferristene distribution was assessed by 2 reviewers and adverse events were recorded. RESULTS: More than 50% of the small bowel segments analyzed were filled with ferristene in 30 patients in the fast ingestion group and in 28 patients in the standard ingestion group. One patient in each group experienced nausea and/or vomiting. Some bloating or sensation of fullness was reported by 2 patients in the fast ingestion group and by 3 patients in the standard ingestion group. CONCLUSION: The distribution of ferristene in the small bowel and the safety of the procedure were thus similar in the 2 groups using either a fast ingestion procedure with oral metoclopramide or the more time-consuming standard ingestion procedure.

Evaluation of the clinical safety of gadodiamide injection, a new nonionic MRI contrast medium for the central nervous system: a European perspective.

Gadodiamide injection is a new nonionic paramagnetic, extracellular contrast medium. Its safety at a dose of 0.1 mmol/kg body weight was evaluated in a large European multicentre trial on adults referred for contrast-enhanced MRI of the central nervous system. Safety analysis was performed on 2102 patients, in whom adverse events during and up to 24 h after injection were recorded. Adverse events related or possibly related to gadodiamide injection were observed in 102 patients. Injection-associated reactions classified as discomfort (sensation of heat or coldness, pain or pressure at the injection site) occurred in 37 patients (1.8%) and other adverse events (e.g. headache, nausea) were observed in 65 patients (3.1%). No serious adverse event was reported. Efficacy analysis, performed on 2273 patients, and based on comparison of T1- and T2-weighted images before and T1-weighted images after injection showed that more diagnostic information was obtained after gadodiamide injection in 1424 (62.6%) patients: management of 386 (17.0%) patients was affected by the new information given and that a new diagnosis was made in 755 (33.3%) patients. Gadodiamide injection was shown to be safe and well tolerated. It represents a nonionic alternative to the current products for MRI of the central nervous system.

Oral magnetic particles (ferristene) as a contrast medium in abdominal magnetic resonance imaging.

RATIONALE AND OBJECTIVES: In this phase III study, we evaluated the efficacy and safety of a negative contrast medium, ferristene (oral magnetic particles), among 277 patients undergoing magnetic resonance (MR) imaging of the abdomen. METHODS: Enhanced (800 ml ferristene) MR images were compared with unenhanced MR images in an intraindividual-patient control design. Adverse events were recorded. The examinations were performed on 1.5-T MR systems (T1- and T2-weighted sequences). RESULTS: Ferristene increased the diagnostic information in 50.9% of the patients, particularly in those with abdominal masses, lymphoma, or pancreatic disease. Distribution of ferristene in the stomach, duodenum, jejunum, and ileum was complete or sufficient in 70.5-85% of the studies. In 64% of the patients, we were confident in the MR findings after the use of ferristene, and ferristene disclosed additional findings in 22% of the patients. The incidence of adverse events was 9.0%, but only 3.6% of all patients experienced ferristene-related adverse events (e.g., nausea, vomiting). Most events were mild or moderate in intensity. CONCLUSION: Ferristene was well tolerated, and for 50% of the patients it added useful diagnostic information.

Safety of gadodiamide injection in two different age groups.

A meta-analyses was performed to evaluate the safety of gadodiamide injection (OM-NISCAN) for magnetic resonance imaging in two different age groups (< 65 years; > or = 65 years). Data on vital signs, clinical laboratory parameters, and subjectively experienced adverse events were reviewed for 734 patients included in 19 European Phase II and III trials with gadodiamide injection (0.1 mmol/kg body weight or 0.3 mmol/kg body weight) used in magnetic resonance imaging. One hundred sixty-four patients were 65 years of age or older. No statistically significant differences were shown between this population and the population younger than 65 years of age with respect to vital signs or clinical laboratory parameters. A total of 48 adverse events, discomfort excluded, were reported, with no significant difference in frequency between the two age groups. Injection-associated discomfort was significantly (P = .0025) more frequent in the younger (9.2%) than in the older group (2.5%). Gadodiamide injection is in conclusion a safe contrast medium in older as well as in younger patients.

Gadodiamide in renal transplant patients: effects on renal function and usefulness as a glomerular filtration rate marker.

Gadodiamide at a dose of 0.1 mmol/kg was administered intravenously to 10 renal transplanted patients with stable, impaired, or slowly deteriorating renal function (serum creatinine 194-362 mumol/l). The patients were referred for contrast medium enhanced magnetic resonance imaging to rule out possible graft circulation abnormalities. The excretion of gadodiamide in urine was prolonged as compared with healthy controls. After 120 h 92% of the injected dose was excreted in urine and only 0.4% in faeces. The plasma clearance of gadodiamide was 28.6 +/- (SD) 5.5 ml/min (n = 10), and the renal clearance (0-72 h) was 26.3 ml/min. The renal clearance of 125I-iothalamate for the same time period was 27.9 +/- 5.3 ml/min. Thus, gadodiamide is eliminated by glomerular filtration also in renal transplant patients with moderately to severe impaired renal function, and gadodiamide clearance may serve as an alternative marker for the determination of the glomerular filtration rate. Serum values of creatinine and beta(2)-microglobulin and creatinine clearance were unchanged by gadodiamide and neither was the urinary enzyme excretion significantly changed. These results suggest that the renal tolerance to gadodiamide is good also in renal transplant patients with impaired renal function.

[Clinical evaluation of the tolerability of gadodiamide, a new nonionic contrast agent in MRI of the central nervous system]. / Evaluation clinique de la tolérance du gadodiamide, nouvel agent de contraste non-ionique pour l'IRM du système nerveux central.

Gadodiamide injection (Gd-DTPA-BMA) is a new non-ionic paramagnetic contrast agent for which the safety at the dose 0.1 mmol/kg was evaluated during a European multicentre study on a large population of adult patients who had an MR examination of the central nervous system with contrast medium. The safety analysis was performed on 2,102 patients by recording the adverse events observed during injection and up to 24 hours after the injection. Adverse events due or probably due to gadodiamide injection were observed in 102 patients (4.4%) with injection-site associated discomfort (heat, coldness, pain at the injection site) in 37 patients (1.8%) and adverse events other than discomfort (headache, nausea, vomiting) in 35 patients (3.1%). No adverse events of severe intensity or death were reported during the trial. Gadodiamide injection was shown to be safe and well tolerated and represents a non-ionic alternative to the current products in the field of MR imaging of the central nervous system.

Comparison of the safety of the standard dose and a higher dose of gadodiamide injection for MR imaging of the central nervous system.

This study compared the safety and tolerability of gadodiamide injection at the standard dose (0.1 mmol/kg) and at a higher dose (0.3 mmol/kg) in 289 patients participating in a parallel group multiple independent trial program. All patients had a known or suspected central nervous system lesion necessitating investigation with contrast medium-enhanced magnetic resonance imaging. Safety assessments were made before and after injection of the contrast medium, and 1 day later. No adverse events were judged to be related to gadodiamide injection, and only 3.5% of the patients in each dose group reported adverse events that had an uncertain relationship to the contrast medium; both doses were therefore well tolerated. Headache was the most frequently reported event (2%). There were no significant injection-related changes in neurologic status, laboratory test results, or vital signs. The data obtained indicate that the higher dose of gadodiamide injection is as safe and well tolerated as the standard dose.

A double blind study to evaluate the tolerability of gadodiamide injection and its effect on renal function in patients undergoing cerebral magnetic resonance imaging.

Gadodiamide injection was administered intravenously to 28 patients with cancer undergoing cerebral magnetic resonance imaging (MRI). Two parallel groups were used to evaluate the safety of single doses of 0.1 and 0.3 mmol per kilogram body weight (kgbw). Adverse events, vital signs, blood chemistry, haematology and urinalysis were the principal measures of safety. Four patients, all in the 0.1 mmol kgbw-1 group, experienced a total of six adverse events. No adverse events were reported in the 0.3 mmol kgbw-1 group. No clinically significant changes in blood chemistry, haematology or urinalysis occurred. No significant changes in renal tubular function or glomerular filtration rate were observed after injection at either dose. Overall, this study suggests that gadodiamide injection is a safe and effective contrast medium for use in patients undergoing cerebral MRI at both the 0.1 and 0.3 mmol kgbw-1 doses.

Iodixanol in cardioangiography in patients with coronary artery disease. Tolerability, cardiac and renal effects.

Iodixanol is a new nonionic, dimeric contrast medium. With the addition of 18 mmol/l Na+ and 0.3 mmol/l Ca++ to iodixanol 320 mg I/ml a plasma-isotonic solution was obtained. The purpose was to evaluate the suitability of iodixanol for use in cardioangiography by determining the diagnostic efficacy, patient tolerability, and cardiac and renal side-effects. Initially, 14 patients with coronary artery disease were examined using iodixanol. A double-blind, randomized study was then performed in 72 patients, comparing iodixanol and iohexol. Serum and urine were sampled before the examination, and one and 2 days after. The diagnostic information was good and the number of adverse events low with iodixanol. The patients reported significantly less of a sensation of warmth following injection of iodixanol than iohexol. Our results also indicate that iodixanol 320 mg I/ml influences renal function to a lesser degree than does iohexol 350 mg I/ml. We therefore conclude that isotonic iodixanol is a safe contrast medium for use in cardioangiography.

Iodixanol--a new nonionic dimer--in aortofemoral angiography.

In 26 patients iodixanol, a new nonionic dimer, isotonic to blood in all concentrations, was used as contrast medium in aortofemoral angiography. Half of the patients received contrast medium in a concentration of 270 mg I/ml and the other half 320 mg I/ml. The aim of the trial was to evaluate the safety and tolerability of iodixanol and the radiographic efficacy of the two concentrations. The degree of discomfort, adverse events, changes in serum chemistry parameters, and diagnostic information were assessed. There were no changes or trends of clinical importance in serum chemistry parameters. The side effects were mild and consisted mostly of some sensation of warmth of short duration. No other adverse events were seen. The overall radiographic efficacy did not show any significant difference between the two concentrations. This indicates that iodixanol is safe and well tolerated when used in adult femoral angiography.

Safety and tolerability of iodixanol in healthy volunteers with reference to two monomeric X-ray contrast media.

The low osmolar, non-ionic X-ray contrast media have shown a lower frequency of adverse events than the older ionic ones. In this study changes in routine clinical-chemical parameters in blood and urine, vital signs and adverse events were recorded in six groups of 10 healthy male volunteers receiving either iodixanol, a new non-ionic, dimeric X-ray contrast medium for general vascular use, or one of the two non-ionic, monomeric contrast media iopentol and iopamidol. Minor decreases were observed in the values for haemoglobin, haematocrit and erythrocytes 5 min and 3 days after injection of iodixanol. A minor increase was seen in platelets and total protein after 3 days. A transient increase in serum osmolality was seen 5 min after the injections of iopentol and iopamidol. This was not seen in any iodixanol group. The level of thyrotropin showed an increase in all groups at 3 days. It was back to normal within 21 days. No changes of clinical importance were seen regarding blood pressure, heart rate or ECG in any volunteer. No severe adverse events were reported. All events were of short duration, and of mild or moderate intensity. The results, however, may indicate a lower frequency of adverse events/discomfort after the administration of the dimeric iodixanol than the 2 monomeric contrast media iopentol and iopamidol.

Evaluation of renal function with delayed CT after injection of nonionic monomeric and dimeric contrast media in healthy volunteers.

A new nonionic dimeric contrast medium (CM), iodixanol, was intravenously administered to 40 healthy male volunteers in doses of 0.3-1.2 g of iodine per kilogram of body weight, nonionic monomeric iopamidol and iopentol were administered to 20 others, and the renal effects were studied up to 120 hours after administration. Computed tomography of the kidneys was performed up to 80 hours after injection. Creatinine clearance as an index of the glomerular filtration rate was unchanged with all CM. Urine volume and osmolar clearance increased most with the monomeric CM. The proximal tubular brush border enzyme alkaline phosphatase increased with all CM. The lysosomal enzyme N-acetyl-beta-glucosaminidase increased more with the monomeric CM than with iodixanol. A persistent increased attenuation in the region of the cortex was observed with all CM. Attenuation returned to baseline within 80 hours, with the slowest decline with iodixanol. This delayed cortical enhancement did not correlate with the effects of the CM on the tubular enzyme excretion.