Perflutren lipid microspheres (DMP 115) is a preparation of liposome-encapsulated microspheres containing perflutren that was developed as an ultrasound (US) contrast agent for use in echocardiography to enhance US images (1, 2). In the United States, it is approved by the Food and Drug Administration (FDA) for clinical use in patients with suboptimal echocardiograms to opacify the left ventricular chamber (LV) and to improve the delineation of the left ventricular endocardial border (3).
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 (4-7). 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 (5, 8, 9). Human serum albumin, synthetic polymers and phospholipids have been used to construct the membranes 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. The current clinical application of these agents is in myocardial contrast echocardiography (MCE) (10).
Perfluorocarbons (PFCs) are inert, volatile chemicals and can be encapsulated within microbubbles to provide a stabilizing effect. The extremely low water solubility of PFCs (from 0.19 mol/m3 for n-C3F8 to 2.7 х 10−4 mol/m3 for n-C6F14) sets up an equilibrium in vivo in 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) (11, 12). Perfluorooctyl bromide (C8BrF17), a compound similar to perflutren (C3F8; octafluoropropane or 1,1,1,2,2,3,3,3-octafluoropropane), was first discovered to possess sufficient lipophilicity to be formulated into stable emulsions, but it was developed as an oral agent for negative magnetic resonance imaging of the gastrointestinal tract (13). Perflutren has a boiling point of −37 º C and can be encapsulated as PFC gas within microbubbles (14).
DMP 115 was developed based on the perfluorocarbon liquid/gas-phase shift-based system with perflutren gas encapsulated within lipid microspheres (3, 5). The lipid formulation is a blend of dipalmitoylphosphatidylcholine (DPPC), a methylpoly(ethylene glycol) dipalmitoylphosphatidylethanolamine (MPEG5000 DPPE) and a small amount of negatively charged dipalmitoylphosphatidic acid (DPPA). These components are stored refrigerated under a headspace of perflutren gas before use. The recommended dose for clinical use is 10 µl/kg of body weight by i.v. bolus injection (30-60 sec). A second 10 µl/kg dose may be administered 30 min after the first dose.
Serious cardiopulmonary reactions following the administration of ultrasound microbubble contrast agents have been reported (15). In 2007, the