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OBJECTIVE: : To evaluate BR38, a new microbubble-based blood pool agent for contrast-enhanced ultrasound imaging. MATERIALS AND METHODS: : The size characteristics of BR38 microbubbles were measured by Coulter counting. The backscatter and attenuation coefficients were determined as a function of frequency. Additional measurements included the surface charge, osmolality, viscosity, and resistance to hydrostatic pressure. Extensive pharmacological and toxicological studies were conducted on the final formulation in rats and dogs. The blood levels and elimination of the gaseous component C4F10 were determined in the rabbit. Contrast-enhanced echographic examinations were performed in pigs focusing on the myocardium and the liver. Finally, safety testing and preliminary imaging experiments were performed in a Phase I clinical study in human volunteers. RESULTS: : BR38 suspensions are isotonic, nonviscous, and show a high resistance to hydrostatic pressure. Their backscatter coefficient is high at ≥ 2 MHz and attenuation shows a maximum at 4 MHz, slowly decreasing at higher frequencies. The no adverse effect levels of 1 µL/kg (rats) and 5 µL/kg (dogs) expressed as microbubble gas volume, observed in repeated toxicology studies, correspond to 50 and 250 times the expected imaging dose in human beings (0.02 µL/kg), respectively. No effects on cardiovascular and respiratory parameters were observed in rats and dogs. C4F10 is eliminated within minutes from blood and excreted in expired air. Imaging experiments showed strong and persistent enhancement of the myocardium and the liver. A late phase was observed in the liver, in animals and in human volunteers. No serious adverse events and no significant changes in vital signs, electrocardiographs, and laboratory tests were observed in Phase I human volunteers. CONCLUSIONS: : BR38 shows a very good safety profile. It is characterized by a long persistence and low shadowing. BR38 is a promising ultrasound blood pool agent for noncardiac and cardiac applications including myocardial perfusion imaging.

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The Society of Toxicologic Pathology (STP) has developed the following recommendations for the use of pathology images in compliance with the Code of Federal Regulations (CFR), Volume 21, Part 58 (Good Laboratory Practices [GLP]) and Part 11 (Electronic Records/Signatures). These recommendations include: (1) based on current technologies and practices, pathology images (printed, electronic, or digital) used for data generation (e.g., to make a diagnosis or for morphometric analysis) are raw data that must be authenticated and archived; (2) authentication of an image may be done either by initialing and dating a print of the image or by specifically annotating the electronic image file in compliance with Part 11 regulations; (3) images used for raw data are subject to GLP procedures and controls in order to ensure data integrity including written Standard Operating Procedures, testing/validation of equipment, training of personnel, etc.; (4) validation and/or performance qualification of imaging systems used to support GLP studies must be documented and any exceptions to full validation/qualification must be described in the GLP Compliance Statement for the study; (5) images that are not used for data generation are illustrative images, are not raw data, and generally do not have to be archived; 6) illustrative images should not be used to re-evaluate or supersede the pathologist's diagnosis.

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In vivo gadolinium release was evaluated for MultiHance, Omniscan and Gadovist estimating gadolinium content in liver, kidneys, spleen, femur and brain after single or repeated intravenous administrations to rats at 1 mmol/kg. Gadolinium acetate (GdAc) at a daily dose of 0.03 mmol/kg and physiological saline were used as positive and negative controls, respectively. No changes in blood chemistry, haematology nor histopathology were seen with any of the tested contrast media, whereas an increase in white blood cell count and in serum cholesterol were found after GdAc at 0.18 mmol/kg cumulative dose. Analogously, gadolinium content in target organs (as % of injected dose) after any of contrast media was 100-200 times lower than after GdAc, either after single or repeated administrations. Under these experimental conditions, the rank of residual gadolinium found in these organs was GdAcOmniscan >Gadovist >MultiHance. Depopulation of lymphocytes in periarteriolar lymphatic sheaths (PALS) areas of the spleen was noted in rats treated with a single dose of GdAc sacrificed 24h post-dosing, but not in repeated dose rats sacrificed 48 h after last dosing. It was, therefore, concluded that this was a transient phenomenon and that PALS are rapidly repopulated with lymphocytes. With all contrast media, gadolinium content after a 2-day washout following a 3-week repeated administration period was lower than the amount found 24h after a single administration. Accordingly, the observed gadolinium content in organs should actually be in a complexed form (possibly the injected complex) which is subjected to elimination.

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The purpose of this paper is to discuss the requirement of the audit trail to track changes made to the histopathology data, in order to be compliant with the Code of Federal Regulations (CFR), Volume 21, for both Part 58 (Good Laboratory Practices [GLP]) and Part 11 (Electronic Records/Signatures).

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