US EPA

6321030 

Book/Book Chapter 

Perflexane-Lipid Microspheres 

Cheng, KT 

2004 

National Center for Biotechnology Information (US) 

Bethesda (MD) 

Molecular Imaging and Contrast Agent Database (MICAD) 

English 

20641960 

Perflexane-lipid microspheres (AFO150) is a preparation of perfluorocarbon (PFC)-based microbubbles that was developed as an ultrasound (US) contrast agent for use in echocardiograms to enhance US images (1-3). In the United States, it was approved by the Food and Drug Administration in 2002 for clinical use in echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. However, AFO150 is not currently available for clinical applications. US contrast agents or echopharmaceuticals are designed to change the attenuation (absorption, reflection, and refraction) or impedance (resistance to sound propagation) of sound for enhancing the differentiation of the signal (echo) of a target organ from that of the surrounding tissue (3-6). Gas-liquid emulsions (microbubbles or gaseous particles) are highly echogenic invivo because of the nonlinear rarefaction and compression effects that lead to volume pulsations of microbubbles (3, 7, 8). Human serum albumin, synthetic polymers and phospholipids have been used to construct the membrane of these bubbles. Microbubble preparations of various formulations have been developed, and their clinical usefulness depends very much on the size and stability of these bubbles in vivo. PFCs are inert, volatile chemicals and can be encapsulated within the microbubbles to provide a stabilizing effect. The extremely low water solubility of PFCs sets up an equilibrium in vivo where the water-soluble gases diffuse in and out of the microbubble, but the PFC vapor counterbalances the surface tension and blood pressure forces that push the gases inside the bubble toward dissolution. As a result, the combined properties of the microbubble shell and the PFC gas inside determine the stability and output signal of each microbubble in vivo. PFC emulsions were initially studied as oxygen carriers (blood substitutes) (9, 10). Perfluorooctyl bromide (C8BrF17), a compound similar to perflexane (C6F14), was first discovered to possess sufficient lipophilicity to be formulated into stable emulsions but was developed as an oral agent for negative magnetic resonance imaging of the gastrointestinal tract (11). AFO150 was developed based on the concept of osmotic stabilization of the microbubbles by a mixture of nitrogen gas and perflexane (1-3). The preparation formulation uses a semi-synthetic phospholipid, dimyristoylphosphatidylcholine (DMPC), for forming the lipid microsphere shell and hydroxyethyl starch to serve as a mold or template for the desired bubbles. The commercial product contains a powder of 200 mg of spray-dried, micrometer-sized hollow and porous spheres under a gas mixture of nitrogen and perflexane. Upon reconstitution with sterile water (5.9-13.7 × 108 microspheres/ml) and i.v. administration to a patient, the preparation produces approximately 3-µm microbubbles with a single layer of phospholipid membrane that encloses the perflexane/nitrogen gases within the targeted organ. Serious cardiopulmonary reactions following the administration of ultrasound microbubble contrast agents have been reported (12). In 2007, the US FDA requested that warnings emphasizing the risk for serious cardiopulmonary reactions be added to the labeling of these agents. The uses of these agents are contraindicated in patients with unstable cardiopulmonary status.