Safety of Lumason® (SonoVue®) in special populations and critically ill patients.

Evidence for the safe use of Lumason® (SonoVue®), an ultrasound enhancing agent (UEA), in special patient populations is critical to enable healthcare professionals to make informed decisions concerning its use in such patients. Herein, we provide insight on the safety and tolerability of Lumason® in special patient populations. Findings are presented from clinical pharmacology studies conducted in patients with compromised cardiopulmonary conditions, from a retrospective study performed in critically ill patients, and from post-marketing surveillance data from over 20 years of market use of Lumason® (SonoVue®). No detrimental effects of Lumason® on cardiac electrophysiology were observed in patients with coronary artery disease (CAD), and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure. Similarly, no effects on several assessments of pulmonary function (e.g., FVC) were observed in patients with chronic obstructive pulmonary disease (COPD), and no clinically meaningful changes in O2 saturation or other safety parameters were observed after administration of Lumason® to patients with diffuse interstitial pulmonary fibrosis (DIPF). The retrospective study of critically ill patients revealed no significant difference for in-hospital mortality between patients administered Lumason® for echocardiography versus those who had undergone echocardiography without contrast agent. Post-marketing surveillance revealed very low reporting rates (RR) for non-serious and serious adverse events and that serious hypersensitivity reactions were rare. These findings confirm that Lumason® is a safe and well tolerated UEA for use in special populations and critically ill patients.

The Benefits of High Relaxivity for Brain Tumor Imaging: Results of a Multicenter Intraindividual Crossover Comparison of Gadobenate Dimeglumine with Gadoterate Meglumine (The BENEFIT Study).

BACKGROUND AND PURPOSE: Gadobenate dimeglumine (MultiHance) has higher r1 relaxivity than gadoterate meglumine (Dotarem) which may permit the use of lower doses for MR imaging applications. Our aim was to compare 0.1- and 0.05-mmol/kg body weight gadobenate with 0.1-mmol/kg body weight gadoterate for MR imaging assessment of brain tumors. MATERIALS AND METHODS: We performed crossover, intraindividual comparison of 0.1-mmol/kg gadobenate with 0.1-mmol/kg gadoterate (Arm 1) and 0.05-mmol/kg gadobenate with 0.1-mmol/kg gadoterate (Arm 2). Adult patients with suspected or known brain tumors were randomized to Arm 1 (70 patients) or Arm 2 (107 patients) and underwent 2 identical examinations at 1.5 T. The agents were injected in randomized-sequence order, and the 2 examinations were separated by 2-14 days. MR imaging scanners, imaging sequences (T1-weighted spin-echo and T1-weighted high-resolution gradient-echo), and acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images for diagnostic information (degree of definition of lesion extent, lesion border delineation, visualization of lesion internal morphology, contrast enhancement) and quantitatively for percentage lesion enhancement and lesion-to-background ratio. Safety assessments were performed. RESULTS: In Arm 1, a highly significant superiority (P < .002) of 0.1-mmol/kg gadobenate was demonstrated by all readers for all end points. In Arm 2, no significant differences (P > .1) were observed for any reader and any end point, with the exception of percentage enhancement for reader 2 (P < .05) in favor of 0.05-mmol/kg gadobenate. Study agent-related adverse events were reported by 2/169 (1.2%) patients after gadobenate and by 5/175 (2.9%) patients after gadoterate. CONCLUSIONS: Significantly superior morphologic information and contrast enhancement are demonstrated on brain MR imaging with 0.1-mmol/kg gadobenate compared with 0.1-mmol/kg gadoterate. No meaningful differences were recorded between 0.05-mmol/kg gadobenate and 0.1-mmol/kg gadoterate.

[Multicenter analysis of tolerance and clinical safety of the extracellular MR contrast agent gadobenate dimeglumine (MultiHance)]. / Multizentrische Analyse der Verträglichkeit und klinischen Sicherheit des extrazellulären MR-Kontrastmittels Gadobenat-Dimeglumin (MultiHance).

PURPOSE: Retrospective analysis of the occurrence of adverse events and the diagnostic efficacy of a paramagnetic contrast agent with weak intermittent protein binding and high relaxivity. MATERIALS AND METHODS: Postmarketing surveillance studies for gadobenate dimeglumine (MultiHance, BRACCO Altana Pharma, Constance) were conducted in Germany between 1998 and 2006 and then retrospectively analyzed. Demographic data, relevant comorbidities, and allergies were recorded. The safety and tolerability of MultiHance were logged on a standardized data sheet. RESULTS: A total of 38,568 patients were included in the study. 829 patients (2.1%) had a known intolerance against contrast media. The examined regions included the central nervous system, the liver, and the vascular bed. The injection rate with automated injectors (n = 10456) varied between 1.0 und 3.0 ml/sec in 86.5% of patients. Adverse events totaled 1.2%. 11 patients (0.03%) experienced serious adverse events. The most frequent findings were nausea, vomiting and a feeling of warmth. CONCLUSION: MultiHance is a safe and very well tolerated contrast agent for magnetic resonance imaging (MRI) with a profile and frequency of adverse events similar to other extracellular MR contrast materials.

Diagnostic efficacy of SonoVue, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study.

The purpose of this study was to demonstrate the improvement in diagnostic quality and diagnostic accuracy of SonoVue microbubble contrast-enhanced ultrasound (CE-US) versus unenhanced ultrasound imaging during the investigation of extracranial carotid or peripheral arteries. 82 patients with suspected extracranial carotid or peripheral arterial disease received four SonoVue doses (0.3 ml, 0.6 ml, 1.2 ml and 2.4 ml) with Doppler ultrasound performed before and following each dose. Diagnostic quality of the CE-US examinations was evaluated off-site for duration of clinically useful contrast enhancement, artefact effects and percentage of examinations converted from non-diagnostic to diagnostic. Accuracy, sensitivity and specificity were assessed as agreement of CE-US diagnosis evaluated by an independent panel of experts with reference standard modality. The median duration of clinically useful signal enhancement significantly increased with increasing SonoVue doses (p< or =0.002). At the dose of 2.4 ml of SonoVue, diagnostic quality evaluated as number of inconclusive examinations significantly improved, falling from 40.7% at baseline down to 5.1%. Furthermore, SonoVue significantly (p<0.01) increased the accuracy, sensitivity and specificity of assessment of disease compared with baseline ultrasound. SonoVue increases the diagnostic quality of Doppler images and improves the accuracy of both spectral and colour Doppler examinations of extracranial carotid or peripheral arterial disease.

Magnetic resonance imaging of metastatic disease to the brain with gadobenate dimeglumine.

Seventy-four patients with one to eight proven intraaxial brain metastases received a total cumulative dose of 0.2 mmol/kg bodyweight gadobenate dimeglumine, administered as sequential injections of 0.05, 0.05 and 0.1 m mol/kg over a 20-min period. MR imaging was performed before the first administration (T2- and T1-weighted sequences) and after each injection of contrast agent (T1-weighted sequences only). Quantitative assessment of images revealed significant (P <0.01) dose-related increases in lesion-to-brain (L/B) ratio and percent enhancement of lesion signal intensity. Qualitative assessment by two independent, blinded assessors revealed additional lesions in 22%, 25% and 38% (assessor 1) and 29%, 32% and 34% (assessor 2) of patients after each cumulative dose when compared with combined T1- and T2-weighted pre-contrast images. Significantly more lesions (P < 0.01) were noted by both assessors after the first injection and by one assessor after each subsequent injection. For patients with just one lesion observed on unenhanced T1- and T2-weighted images, additional lesions were noted in 12%, 16% and 28% of patients by assessor 1 following each dose and in 24%, 27% and 30% of patients by assessor 2. Contemporaneously, diagnostic confidence was increased and lesion conspicuity improved over unenhanced MRI. For patients with one lesion observed after an initial dose of 0.05 mmol/kg, additional lesions were noted by assessors 1 and 2 in 9.1% and 11.8% of patients, respectively, after a cumulative dose of 0.1 mmol/kg and in a further 9.1% and 5.9% of patients, respectively, after a cumulative dose of 0.2 mmol/kg. No safety concerns were apparent.

Gadobenate dimeglumine-enhanced magnetic resonance imaging of intracranial metastases: effect of dose on lesion detection and delineation.

Seventy-four patients with one to eight proven intraaxial metastatic lesions to the brain received a total gadobenate dimeglumine dose of 0.3 mmol/kg of body weight, administered as three sequential bolus injections of 0.1 mmol/kg, at 10-minute intervals over a 20-minute period. Quantitative and qualitative assessments of efficacy were performed after each injection and a full evaluation of safety was conducted. Cumulative dosing produced significant (P < 0.01) dose-related increases in lesion-to-brain (L/B) ratio and lesion signal intensity (SI) enhancement. Two independent, blinded assessors noted additional lesions, compared to unenhanced images in 31% and 33%, 49% and 42%, and 50% and 48% of patients after each cumulative dose, respectively. Significantly more lesions were noted after the first injection, compared to unenhanced images (P = 0.002 and P < 0.001; assessors 1 and 2, respectively), and after a second injection, compared to the first (P < 0.001 and P = 0.039; assessors 1 and 2, respectively). Neither assessor noted significantly more lesions after the third injection. For patients with just one lesion observed on unenhanced T1- and T2-weighted images, additional lesions were noted by assessors 1 and 2 for 27% and 26%, 48% and 35%, and 42% and 41% of patients, respectively, following each injection. Contemporaneously, diagnostic confidence was increased and lesion conspicuity improved over unenhanced magnetic resonance imaging (MRI). For patients with one lesion observed after 0.1 mmol/kg of gadobenate dimeglumine, additional lesions were noted for 24% and 17% of patients (assessors 1 and 2, respectively) following a second 0.1 mmol/kg injection. Only assessor 2 noted additional lesions following the third 0.1 mmol/kg injection. The findings of on-site investigators concurred with those of the two off-site assessors. No safety concerns were apparent.

Safety assessment of gadobenate dimeglumine (MultiHance): extended clinical experience from phase I studies to post-marketing surveillance.

Clinical trials completed by September 2000 on gadobenate dimeglumine (Gd-BOPTA; MultiHance) included 2540 adult and pediatric subjects that were administered this agent. For adult patient volunteers, the overall incidence of adverse events (AEs) was 19.8%, although marked study- and indication-related differences were apparent. Events potentially related to Gd-BOPTA administration were reported for 15.1% of adult patients. The vast majority of AEs were non-serious, mild, transient, and self-resolving. Headache, injection site reaction, nausea, taste perversion, and vasodilation were the most common AEs, reported with a frequency of between 1.0% and 2.6%. Serious AEs potentially related to Gd-BOPTA were reported for five (0.2%) patients overall. Controlled studies revealed no differences between Gd-BOPTA and other gadolinium chelates or placebo in the incidence and type of AEs. Similarly, no differences with respect to adult patients and/or comparator were noted in studies on pediatric subjects and subjects with renal or liver insufficiency. Post-marketing surveillance of approximately 100000 doses revealed an overall AE incidence of < 0.03% with serious AEs reported for < 0.005% of patients.

SonoVue in transcranial Doppler investigations of the cerebral arteries.

BACKGROUND AND PURPOSE: The authors investigated the safety and diagnostic potential of a new ultrasound contrast agent (SonoVue) using transcranial color-coded duplex sonography (TCCS). METHODS: Forty patients were enrolled in a multicenter, open-label (on-site), blind (off-site), randomized, dose-ranging crossover study. SonoVue was administered as an intravenous bolus injection of 4 different dosages (0.3, 0.6, 1.2, and 2.4 mL). Efficacy was evaluated as (1) off-site assessment of global quality of the Doppler investigation (based on color or power Doppler images and spectral analysis) at baseline and following each dose of SonoVue according to a 4-point scale (from very poor to excellent imaging of blood flow) and (2) duration of clinically useful signal enhancement and color or power Doppler visualization of blood flow. Additional on-site efficacy assessments performed following each dose of SonoVue included confidence in diagnosis and global consequences of contrast enhancement on diagnosis. Safety evaluations included clinical laboratory tests, neurological examination, injection site tolerability, and incidence of adverse events and their relationship to the study agent. RESULTS: All doses of SonoVue significantly improved the global quality of Doppler examinations (P < .05). The median duration of clinically useful enhancement was dose related (P < .001) and ranged from 2 to 6 minutes at the highest dose. The administration of the contrast agent changed a nondiagnostic study to a diagnostic one in 66% of patients and increased the confidence in diagnosis in 74% of cases. No serious adverse events were recorded following SonoVue administration. The observed adverse reactions were all transient and mild in intensity. CONCLUSIONS: The results obtained from this multicenter study demonstrate that the administration of SonoVue to patients with ischemic cerebrovascular disease who undergo TCCS examination of cerebral vessels improves the visualization of intracranial arteries, providing a dose-dependent contrast enhancement and a clinically useful duration of signal enhancement related to the dose. During this multicenter study, SonoVue proved to be a safe and well-tolerated compound.

Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis.

RATIONALE AND OBJECTIVES: To present the results of two studies conducted to evaluate the pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with various degrees of renal impairment. METHODS: In these two open-label, single-dose, phase I studies, a 50-mL dose of iomeprol 400 was administered intravenously to a total of 30 subjects of either sex. In study 1, six healthy volunteers with normal renal function, six patients with mild renal failure, six patients with moderate renal failure, and four patients with severe renal failure were enrolled. In study 2, eight patients with end-stage renal disease requiring hemodialysis were enrolled. Safety was determined by predose and postdose (up to 10 days) measurement of vital signs, hematology, blood chemistry, urinalysis, electrocardiogram, physical examinations, and the incidence of adverse events. Pharmacokinetics was determined by measuring iomeprol levels in plasma, urine, feces, and dialysate samples, by using a validated high-performance liquid chromatography assay, up to 7 days after administration. RESULTS: The plasma concentration of iomeprol declined biexponentially in both healthy subjects and patients. As expected, mean body and renal clearances decreased progressively with increasing renal impairment, with a significant correlation with the glomerular filtration rate. The elimination half-life increased progressively with increasing renal impairment. The extraction efficiency of dialyser was estimated as approximately 40%, and dialysis clearance of iomeprol was approximately 1.26 mL. min-1. kg-1 (80.6 mL/min), slightly less than the body clearance previously observed in healthy subjects. It appears that dialysis is almost as efficient as renal function in healthy subjects in the removal of iomeprol. After a single dialysis session, approximately 58% of the dose was recovered in dialysate. Mild to moderate adverse events were reported by 17 of 30 subjects; none was clinically meaningful. One serious adverse event, unrelated to iomeprol, was reported. No clinically meaningful findings were noted for other safety parameters. CONCLUSIONS: Iomeprol was almost completely eliminated both in patients with renal impairment and in patients receiving dialysis. No dose adjustment appears to be necessary either in patients with renal impairment or with end-stage renal disease requiring hemodialysis. In this risk population, iomeprol 400 was safe and well tolerated.

Clinical experience with iomeprol in myelography and myelo-CT: clinical pharmacology and double-blind comparisons with iopamidol, iohexol, and iotrolan.

RATIONALE AND OBJECTIVES: To evaluate iomeprol, a new nonionic iodinated contrast medium, as a contrast agent for myelography and to compare it with iopamidol, iohexol, and iotrolan. METHODS: An extensive clinical program was conducted on more than 600 patients to assess iomeprol's pharmacokinetics, tolerability, safety, and efficacy after intrathecal injection. RESULTS: Pharmacokinetics study results showed that after intrathecal administration iomeprol is completely absorbed from the cerebrospinal fluid compartment; once absorbed into the systemic circulation, it is rapidly excreted, unmetabolized, by glomerular filtration. Dose-finding studies showed that the opacification produced by iomeprol depends on the injected dose. Although a dose-dependent increase in efficacy was observed, no differences in neurotolerability and safety were detected between the doses tested. Doses of iomeprol greater than 3 g I did not cause a greater incidence of adverse events and produced significantly better contrast efficacy. Comparative clinical trials showed that iomeprol and iopamidol, iohexol, and iotrolan always provided adequate opacification of the subarachnoid space, both in conventional myelography and myelo-CT, with adequate delineation of normal structures and pathologic processes. No serious adverse events occurred up to a total dose of 4.5 g I. No differences between the agents with regard to tolerance, adverse events, and effects on vital signs, physical examination, and neurologic examination were observed. CONCLUSIONS: Iomeprol is safe and effective and can be recommended for myelography and myelo-CT.

Iomeprol: current and future profile of a radiocontrast agent.

RATIONALE AND OBJECTIVES: To review the safety and efficacy profiles of iomeprol by examining the most indicative comparative clinical studies of iomeprol with widely used low-osmolar ionic or nonionic contrast agents, and to illustrate the recent development in iomeprol liposomal formulations for liver imaging and intravascular enhancement. METHODS: Randomized, double-blind, comparative studies were performed of iomeprol versus iopamidol, iopromide, ioxaglate, iopentol, iodixanol, ioversol, and iohexol. In all studies, safety controls included pre- and postadministration physical examinations, monitoring of vital signs, electrocardiography, clinical laboratory investigations, and 24- or 72-hour postadministration monitoring of patients for adverse events. Technically adequate images were rated for diagnostic efficacy by masked assessors. RESULTS: Iomeprol showed similar safety and diagnostic efficacy compared with the nonionic monomers iopamidol, iohexol, and ioversol, and no statistically significant differences were observed. No differences in diagnostic efficacy between iomeprol and iopromide were observed, but in one study on 1,200 patients, the incidence of adverse events and adverse reactions was significantly higher with iopromide than with iomeprol. Iomeprol caused significantly less heat/pain than iopentol in one study; it showed similar safety and tolerability to the nonionic dimer iodixanol, the two agents causing no or modest, superimposable pain and heat sensation at injection and showing similar renal tolerability after intra-arterial injection. A comparison of iomeprol versus ionic dimer ioxaglate in 2,000 patients undergoing percutaneous coronary interventions showed that the incidence of thrombus-related events was similar with the two agents, but ioxaglate caused a significantly higher incidence of allergy-like reactions. First results with iomeprol-containing liposomal formulations show that these agents may facilitate the CT assessment of intrahepatic malignancies and CT angiography procedures. CONCLUSIONS: The overall results of numerous randomized, double-blind, comparative clinical studies in a variety of indications show that the diagnostic efficacy of iomeprol solutions does not differ significantly from that of the low-osmolar contrast media available on the marketplace when similar iodine strengths are used, although iomeprol may have better tolerability and safety than the ionic dimer and some of the nonionic monomers in selective applications. First results obtained with iomeprol-containing liposomal formulations are promising and may foster additional clinical testing.

Clinical safety of SonoVue, a new contrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease.

RATIONALE AND OBJECTIVES: To evaluate the safety profile of SonoVue, a new echo-contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles, in healthy volunteers and in patients with chronic obstructive pulmonary disease (COPD). METHODS: Safety and tolerability of SonoVue were evaluated in 66 healthy volunteers during two placebo-controlled phase I studies (a single intravenous ascending-dose study in 36 volunteers given SonoVue doses of 0.003 to 0.12 mL/kg and a multiple-dose study in 30 subjects given cumulative doses of 0.15 to 0.6 mL/kg) and in 12 patients with COPD of various degrees of clinical severity, who were given SonoVue at a dosage of 4 mL (corresponding to 0.057 mL/kg in a 70-kg patient). Adverse events were monitored up to 48 to 72 hours after administration. All volunteers underwent extensive safety assessments (monitoring of vital signs, electrocardiogram, blood oxygen saturation, laboratory assessments, and Mini-Mental test) up to 24 to 72 hours after administration. In addition, patients with COPD underwent specific lung function tests, such as forced expiratory volume, forced vital capacity, and forced midexpiratory flow. RESULTS: No serious adverse events occurred throughout the study. All nonserious adverse events were minor, mild, and rapidly self-resolving. No difference in the incidence of adverse events was observed among the various dosages of SonoVue and between SonoVue and placebo. There were no clinically significant changes in any of the safety assessments. No statistically significant differences between SonoVue and placebo were observed in mean forced expiratory volume, forced vital capacity, or forced midexpiratory flow levels. No substantial changes from baseline in blood oxygen saturation were observed for either study agent at any postinjection time point. CONCLUSIONS: SonoVue showed a good safety profile both in healthy subjects and in patients with COPD.

Detection of malignant primary hepatic neoplasms with gadobenate dimeglumine (Gd-BOPTA) enhanced T1-weighted hepatocyte phase MR imaging: results of off-site blinded review in a phase-II multicenter trial.

OBJECTIVE: To investigate the efficacy of gadobenate dimeglumine (Gd-BOPTA) enhanced MR imaging for the detection of liver lesions in patients with primary malignant hepatic neoplasms. MATERIALS AND METHODS: Thirty-one patients with histologically proven primary malignancy of the liver were evaluated before and after administration of Gd-BOPTA at dose 0.05 or 0.10 mmol/kg. T1-weighted spin echo (T1W-SE) and gradient echo (T1W-GRE) images were evaluated for lesion number, location, size and confidence by three off-site independent reviewers and the findings were compared to reference standard imaging (intraoperative ultrasound, computed tomography during arterial portography or lipiodol computed tomography). Results were analyzed for significance using a two-sided McNemar's test. RESULTS: More lesions were identified on Gd-BOPTA enhanced images than on unenhanced images and there was no significant difference in lesion detection between either concentration. The largest benefit was in detection of lesions under 1 cm in size (7 to 21, 9 to 15, 16 to 18 for reviewers A, B, C respectively). In 68% of the patients with more than one lesion, Gd-BOPTA increased the number of lesions detected. CONCLUSION: Liver MR imaging after Gd-BOPTA increases the detection of liver lesions in patients with primary malignant hepatic neoplasm.

Evaluation of the accuracy of gadobenate dimeglumine-enhanced MR imaging in the detection and characterization of focal liver lesions.

OBJECTIVE: We evaluated the extent to which hepatic lesion characterization and detection is improved by using gadobenate dimeglumine for enhancement of MR images. MATERIALS AND METHODS: Eighty-six patients were imaged before gadobenate dimeglumine administration, immediately after the 2 mL/sec bolus administration of a 0.05 mmol/kg dose (dynamic imaging), and at 60-120 min after the IV infusion at 10 mL/min of a further 0.05 nmol/kg dose (delayed imaging). The accuracy for lesion characterization was assessed for a total of 107 lesions. Sensitivity for lesion detection was assessed for a total of 149 lesions detected on either intra-operative sonography, iodized oil CT, CT during arterial portography, or follow-up contrast-enhanced CT as the gold standard. RESULTS: The accuracy in differentiating benign from malignant liver lesions increased from 75% and 82% (the findings of two observers) on unenhanced images alone, to 89% and 80% on dynamic images alone (p<0.001, p = 0.8), and to 90.7% when combining the unenhanced and dynamic image sets (p<0.001, p = 0.023). Delayed images did not further improve accuracy (90% and 91%; p = 0.002, p< 0.05). A similar trend was apparent in terms of accuracy for specific diagnosis: values ranged from 49% and 62% on unenhanced images alone, to 76% and 70% on combined unenhanced and dynamic images (p<0.001, p = 0.06), and to 75% and 70% on inclusion of delayed images (p<0.001, p = 0.12). The sensitivity for lesion detection increased from 77% and 81% on unenhanced images alone, to 87% and 85% on combined unenhanced and dynamic images (p = 0.001, p = 0.267), and to 92% and 89% when all images were considered (p<0.001, p = 0.01). CONCLUSION: Contrast-enhanced dynamic MR imaging with gadobenate dimeglumine significantly increases sensitivity and accuracy over unenhanced imaging for the characterization of focal hepatic lesions, and delayed MR imaging contributes to the improved detection of lesions.

Focal liver lesions: evaluation of the efficacy of gadobenate dimeglumine in MR imaging--a multicenter phase III clinical study.

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

Safety and pharmacokinetics of a new liposomal liver-specific contrast agent for CT: results of clinical testing in nonpatient volunteers.

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of BR21, a liposome-encapsulated iomeprol formulation, in nonpatient volunteers. METHODS: This was a single-blind, placebo-controlled, ascending dose study in 30 adult, male nonpatient volunteers, randomized to receive a single intravenous bolus (2 mL/s) of BR21 (0.5, 1.0, 1.5, 2.0, and 2.5 mL/kg, four volunteers per dose level) or matched volumes of placebo (0.9% saline, 10 volunteers). The safety controls performed consisted of preand postdose complete physical examinations, measurement of vital signs, electrocardiographic controls, clinical laboratory investigations (hematology, serum chemistry, and urinalysis), and monitoring of adverse events. The safety controls and monitoring of subjects for adverse events continued up to 7 days after the dose. For pharmacokinetic analysis, the determination of total iomeprol content was performed by a high-performance liquid chromatography assay procedure in blood, urine, and fecal samples collected before the dose and serially after the dose, up to 120 hours. RESULTS: No serious adverse events occurred throughout the study. All nonserious adverse events were minor and mild in intensity and rapidly resolved without treatment. No difference in the incidence of adverse events was observed among the various doses of BR21 and between BR21 and placebo. There were no clinically significant changes in vital signs, electrocardiographic parameters, or clinical laboratory findings. Iomeprol blood level decay can be described by a three-exponential function, consistent with a distribution phase (range, t1/2 0.12-0.21 hours), a fast elimination phase (range, t1/2 1.2-1.5 hours), and a slow elimination phase from a deep compartment (range, t1/2 3.3-4.5 hours). There was an apparent linearity in the relation between the area under the curve and the dose. Urinary elimination of unchanged iomeprol accounted for 89% to 90% of injected dose within 24 hours. CONCLUSIONS: BR21 appeared to be safe and well tolerated in nonpatient subjects. Its pharmacokinetic profile was compatible with nonspecific distribution into the extracellular fluid space and specific distribution into a deep compartment.

Hepatocellular carcinoma: correlation between gadobenate dimeglumine-enhanced MRI and pathologic findings.

RATIONALE AND OBJECTIVES: To correlate the appearance of hepatocellular carcinoma on delayed (60 minutes) postcontrast T1-weighted gradient echo images with the mode of action of gadobenate dimeglumine (Gd-BOPTA) and the anatomic and pathologic characteristics of the lesions. METHODS: A total of 34 patients with hepatocellular carcinoma and varying degrees of diffuse liver disease were studied. T2-weighted spin echo and T1-weighted spin echo and gradient echo images were acquired before and 60 minutes after the intravenous administration of 0.1 mmol/kg Gd-BOPTA. Qualitative and quantitative evaluations of the images were performed and correlated with histologic findings. The quantitative evaluation, performed on T1-weighted gradient echo images, looked at the percentage increase of liver enhancement after Gd-BOPTA administration, the lesion-to-liver contrast/noise (C/N) ratio before and after Gd-BOPTA administration, and the C/N variation after Gd-BOPTA administration. Qualitative assessment considered the morphologic features of the lesions as well as the visual variation of contrast before and after Gd-BOPTA administration. Finally, a histologic evaluation was made of the degree of differentiation of the lesions and of the presence of fatty metaplasia, necrosis, bile, or intratumoral peliosis. RESULTS: Among the parameters affecting lesion identification were the extent of liver function, degree of vascularization, residual functionality of the tumor cells, and characteristics of the neoplastic tissue. Positive correlations (Spearman coefficients = 0.359 and 0.393, respectively) were observed precontrast between the degree of liver failure and the amount of contrast noise, and postcontrast between the amount of intralesional fatty metaplasia and the extent to which lesion conspicuity worsened after Gd-BOPTA administration. An inverse correlation (Spearman coefficient = -0.330) was observed between the degree of lesion differentiation and the visible appearance after Gd-BOPTA administration, with well-differentiated lesions tending toward worsened conspicuity postcontrast. A statistically significant difference (P = 0.001) was observed in the mean precontrast C/N ratio for lesions later showing unchanged conspicuity and worse conspicuity on postcontrast images, respectively. Marked variation (P = 0.019) was also observed between Child A and B cirrhotic patients for the degree of hepatic enhancement on postcontrast images. CONCLUSIONS: The results suggest that liver parenchyma signal intensity is influenced by the extent to which liver function is compromised, that residual hepatocytic functionality permits Gd-BOPTA uptake by certain lesions and that this uptake might subsequently impair the observed C/N ratio on delayed images, and that the worsening of lesion conspicuity on postcontrast images is influenced also by high quantities of intralesional fatty metaplasia.