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.

Multi-centre clinical study evaluating the efficacy of SonoVue (BR1), a new ultrasound contrast agent in Doppler investigation of focal hepatic lesions.

OBJECTIVES: SonoVue is a new ultrasound contrast agent, which consists of stabilised microbubbles of a sulphur hexafluoride gas. The aim of the study was to assess its efficacy in the Doppler investigation of focal hepatic lesions. MATERIALS AND METHODS: Seventy patients with focal liver tumours were studied. Four doses (0.3, 0.6, 1.2 and 2.4 ml) of SonoVue were administered intravenously with at least 10 min delay between each injection. A complete colour/power and spectral Doppler imaging investigation of the lesions was performed at baseline pre-dosing and after each SonoVue injection. All examinations were recorded on SVHS videotapes. Baseline and post contrast videotapes were reviewed by the on-site (un-blinded) investigators and by two off-site blinded readers (a) to grade the global quality of the Doppler scans of the focal lesions vascularity and the normal parenchymal vessels (b) to measure the duration of clinically useful Doppler signal enhancement and (c) to determine the diagnostic accuracy and performance of the enhanced versus unenhanced scans using histopathology, tumour markers, CT and/or MR as the reference standard. RESULTS: A statistically significant improvement was observed at all four SonoVue doses in the off site assessment of global quality of the Doppler examination of tumoral and normal parenchymal vessels in comparison with the baseline (P < 0.05). The median duration of clinically useful enhancement was significantly increased with increasing doses (P < 0.001), ranging between 1.4-2.2 min for the lowest dose and 3.2-3.8 min for the highest dose for the off-site readers. On-site assessment of diagnostic accuracy showed a significant increase in the specificity of the Doppler diagnoses (P < 0.0016) with an increase in the positive and negative predictive values and in the likelihood ratio in differentiating between benign and malignant lesions. Off-site evaluation showed a significant increase in the accuracy of enhanced Doppler diagnosis in comparison with the baseline performance. CONCLUSION: The results suggest that SonoVue is effective in improving the display of tumoral vascularisation and may be useful in the characterisation of focal liver lesions.

Transcranial duplex imaging with a sulfurhexafluoride echocontrast agent: enhancement and diagnostic quality.

BACKGROUND AND PURPOSE: The authors investigate characteristics of ultrasound enhancement and diagnostic quality of a sulfurhexafluorides (SF6)-containing echocontrast agent (SonoVue) in cerebrovascular patients with insufficient temporal bone window by transcranial color-coded duplex (TCCD) sonography. METHODS: Thirty patients (mean age = 62.2 +/- 11.1 years) were enrolled. SF6 was administered intravenously in 4 different doses (0.3, 0.6, 1.2, and 2.4 mL). By videotape analysis, time to contrast appearance, duration of contrast enhancement, and duration of clinically useful signal enhancement were measured. Overall quality of ultrasound investigation was also assessed. RESULTS: Time to contrast appearance ranged from 11 to 74 seconds (mean = 26 seconds). For the 0.3, 0.6, 1.2, and 2.4 mL doses, average times to contrast appearance of 30 +/- 12 seconds, 28 +/- 10 seconds, 23 +/- 8 seconds, and 22 +/- 6 seconds were measured. Duration of TCCD signal enhancement was 438 +/- 169 seconds, 483 +/- 195 seconds, 713 +/- 299 seconds, and 788 +/- 344 seconds for the different doses. Clinically useful enhancement was 160 +/- 124 seconds, 200 +/- 157 seconds, 260 +/- 166 seconds, and 327 +/- 239 seconds. CONCLUSIONS: Administration of SonoVue led to a quality improvement in 21 patients. In TCCD, it optimizes visualization of the cerebral arteries in patients with inadequate bone window. A dose of at least 1.2 mL provides the best enhanced images.

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.

A new Doppler signal enhancing agent for flow assessment in breast lesions.

OBJECTIVE: To determine the diagnostic performance of SonoVue (Bracco) in the enhancement of Doppler signals in breast lesions and in the improvement of diagnostic accuracy. METHODS: This multicenter study included 220 patients undergoing investigations of parenchymal lesions, 40 of which had breast tumors. After a baseline Doppler examination, intravenous doses of 0.3, 0.6, 1.2 and 2.4 ml SonoVue were injected. Doppler signal quality before and after injection was compared. Off-site assessment of the global quality of Doppler signal and duration of clinical useful enhancement, as well as off-site and on-site evaluation of quality of color and spectral Doppler, were performed. On-site evaluation of diagnostic accuracy was also carried out. Safety assessments included monitoring of adverse events up to 24 h following the last injection of SonoVue. RESULTS: On-site evaluations: baseline Doppler was conclusive in only 4/21 carcinomas and in 2/17 benign lesions. Enhanced Doppler improved differential diagnosis in 20/21 carcinomas and in 9/12 benign lesions. Time to color enhancement was 0.55 min for the lowest and 0.35 min for the highest dose. The total duration of enhancement was 3.47 min for the lowest and 5.62 min for the highest dose, respectively. Off-site assessment: SonoVue improved the quality of Doppler blood flow information both in parenchymal and focal lesions. Statistically significant changes from baseline in global quality of Doppler investigations were observed at all four SonoVue doses (P<0.05). The duration of clinically useful signal enhancement increased with doses and a significant dose relationship was obtained (P<0.001). Mild adverse events were observed in two patients only. CONCLUSION: The results obtained from this study, following both off-site and on-site assessment, demonstrate that the administration of SonoVue to patients with focal breast lesions provides significant improvement over the baseline of Doppler signal quality and a clinically useful duration of signal enhancement, related to the dose. SonoVue was shown to be a safe and well-tolerated compound.

Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging.

RATIONALE AND OBJECTIVES: To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound. METHODS: The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection. RESULTS: The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. CONCLUSIONS: SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.

Complement activation on the nasal mucosal surface--a feature of the immediate allergic reaction in the nose.

Complement is a system of functionally linked serum proteins that interact to exert biologic effects in inflammatory and immunologic processes. As part of a larger study with a potential topical antiallergic drug, we measured C3a des Arg and C5a des Arg in 13 patients with seasonal allergic rhinitis and in five nonatopic controls after placebo treatment. After 1 week of placebo treatment, a nasal allergen challenge with increasing doses of pollens was performed in both allergic subjects and controls. A symptom score method was used, and in returned nasal lavage fluid, the activity of C3a des Arg and C5a des Arg was measured. We found that allergen challenge in the allergic subjects induced nasal symptoms concomitantly with increased levels of C3a des Arg and C5a des Arg (P < 0.05). No increases either in symptoms or in the very low base-line levels of C3a des Arg and C5a des Arg were observed in the nonallergic controls. We conclude that the activation of the complement cascade is one part of the vasculature exudative response during the immediate allergic reaction in the upper airways. Because of their biologic potency, these proteins may be an essential part of the exudative response which perpetuates the ongoing inflammatory reaction.

[Dimethindene maleate administered via intramuscular route in man: local and systemic tolerance]. / Maléate de dimétindène, administré par voie intramusculaire chez l'homme: tolérance locale et systémique.

Local and systemic tolerance of dimethindene maleate was studied in 10 healthy volunteers by the intramuscular route (4 mg in 4 ml solvent). Subjective perception of pain and other reported side effects were registered and objective signs at the injection site were assessed repeatedly. Hematologic and biochemical tests were performed before and after completion of the study. Two volunteers complained about local pain immediately and one hour after the injection. An other volunteer developed a small hematoma within 48 hours after injection. No other side effects or adverse reactions were noted. Good tolerance of dimethindene maleate after intramuscular application could thus be established.

[Study by radiolabelling of the residual time of a therapeutic gel in the nasal fossae]. / Etude par radiomarquage de la rémanence d'un gel thérapeutique dans les fosses nasales.

The residence times in the nose of the liquid and gel forms of the same therapeutic preparation were compared in 7 healthy subjects. A 50 microliters drop of the preparation, labelled with Tc99m, was placed down the head of the inferior turbinate, and the kinetics of its clearance from the site of deposition was monotired using a gamma camera, during 60 minutes for the liquid and 120 minutes for the gel. The average times for removal of 50% of the labelled material from the site of deposition were 10.3 minutes and 28.6 minutes for the liquid and gel forms respectively. The slower removal of the gel form is probably due to a mechanical effect, and seems to affect the whole nasal passage. The contact time between the preparation and the mucosa is increased in this galenic form and this should improve the efficiency of the preparation.

Pharmacokinetic study of 14C-letosteine in man after oral intake and steady-state.

Based on previous animal and on preliminary human results a further human study was performed in order to confirm the relevant pharmacokinetic parameters and the lack of accumulation of letosteine after repeated administrations. Thus, six healthy male volunteers were given a single oral dose of 50 mg (100 microCi) 14C-letosteine in form of gelatine capsules. A treatment lasting 11 days to obtain a steady-state was started three days later with three similar daily oral doses of unlabelled letosteine. Then, one capsule of 14C-letosteine was administered again. The radioactivity of blood, plasma, urine and expired air was measured at regular intervals after both radioactive doses. Several pharmacokinetic parameters were calculated for the single oral intake and for the oral intake at steady state. The results show a good absorption rate of letosteine since about 90% of the dose was found in the urine. Elimination was biphasic, with half-lives of about 1 and 4 hours in blood and plasma. No striking differences were recorded between the single oral intake and the oral intake at steady state for the various parameters assessed: Cmax, Tmax, AUC, Aeurine and AeCO2. It was therefore concluded that repeated doses of letosteine did not influence the absorption, the distribution, the metabolism and the elimination processes.

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers.

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.

Effect of one month of lactitol treatment on calcium metabolism in man.

The chronic use of lactitol as a food additive or laxative might adversely affect calcium homeostasis. Its effect on calcium metabolism has been examined in an open cross-over study in 12 volunteers given 20-40 g lactitol per day for one month. Compared to a control period without lactitol, the disaccharide did not alter the urinary excretion of calcium, inorganic phosphate or hydroxyproline, nor did it alter the circulating levels of calcium, phosphate, alkaline phosphatase, parathormone and osteocalcin. Chronic treatment with lactitol in laxative doses had no measurable effect on calcium metabolism in man.

Lactitol: gastrointestinal absorption and effect on blood lactate in healthy volunteers and patients with cirrhosis.

The gastrointestinal absorption of lactitol has been studied in 6 healthy volunteers and 8 patients with cirrhosis. Following administration of lactitol 0.5 g/kg, no lactitol was found in serum. The urinary excretion of lactitol over 24 h ranged from 0.1 to 1.4% of the administered dose (0.46% in cirrhotics and 0.35% in healthy volunteers). Blood D- and L-lactate and plasma glucose did not increase following lactitol. The data indicate that lactitol was poorly absorbed from the gastrointestinal tract in healthy volunteers and patients with cirrhosis, and that the disaccharide did not disturb glucose or lactate homeostasis.