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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Perflutren lipid microspheres

DMP 115
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: November 21, 2007.

Chemical name:Perflutren-lipid microspheresimage 8149121 in the ncbi pubchem database
Abbreviated name:DMP 115
Synonym:Definity® ; octafluoropropane-lipid microspheres; liposome-encapsulated perfluoropane microspheres, YM454, 1,1,1,2,2,3,3,3-octafluoropropane-lipid microspheres
Agent Category:Lipid microspheres
Target:Non-targeted, blood pool
Target Category:Passive nonspecific filling of cardiac chambers
Method of detection:Ultrasound (US)
Source of signal/ contrast:Microbubble and perflutren gas
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

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 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.

Synthesis

[PubMed]

PFCs are inert organic materials initially developed for handling the extremely corrosive uranium fluorides (11, 12, 16). Some PFCs are derived directly from the manufacturing line that led to Teflon and other diverse industrial surfactants. Two major strategies are commonly used in producing PFCs. One strategy is substituting fluorine atoms for hydrogen atoms in the parent hydrocarbon analog by electrochemical fluorination, fluorination by high-valence metal fluorides, or direct fluorination. Another strategy is combining smaller, reactive fluorinated building blocks by telomerization. Perflutren can be produced by fluorination of hexafluoropropylene with cobalt trifluoride (14). Pashkevish et al. (14) also described the synthesis of perflutren by high-temperature reaction of graphite with fluorine in a fluidized bed.

Egg phosphatidylcholine and synthetic phospholipids have been used to produce the microbubbles in the emulsion preparation. The commercial preparation of DMP 115 uses a mixture of DPPC, MPEG5000 DPPE, and DPPA to form the lipid shell (3). Immediately before use, the vial that contains the lipid mixture with a headspace of perflutren gas is agitated in a calibrated mechanical shaker for 45 s to produce a suspension of PFC bubbles (1.1-3.3 µm in size) within a lipid shell. If the preparation is not used within 5 min, the lipid microspheres must be resuspended by 10 s of hand agitation (inverting the vial).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Moran et al. (17) reported the in vitro acoustic characteristics of DMP 115 and 3 other US contrast agents in saline. The study found that, despite the different shell characteristics and gas compositions, these agents exhibited remarkably similar acoustic characteristics at 30 MHz. DMP 115 exhibited a peak mean backscatter power at concentrations between 1 х 106 and 10 х 106 microbubbles/ml. At concentrations lower than this, mean backscatter power decreased in a linear manner.

Sboros et al. (18) found that DMP 115 provided a constant number of scattering events per unit volume of suspension in water over acoustic pressures in the range of 0.2 to 1.5 MPa.

Toledo et al. (19) studied the feasibility of real-time three-dimensional echocardiography (RT3DE) with contrast enhancement in 9 isolated rabbit hearts. Administration of 1.3 ml DMP 115 in 25 ml of saline and infused at 16-25 ml/h showed clearly visible and uniform dynamic changes in myocardial video-intensity in all LV image slices at the 1.6-MHz transmit frequency (19).

Animal Studies

Rodents

[PubMed]

Miller et al. (20) studied the potential cardiomyocyte injury induced by MCE in rats at high US mechanical index (MI) values greater than the recommended value of 0.8 for general clinical use. The study found that cardiomyocyte injury was not significant at 1.1-MPa end-systole triggering (MI = 0.9). At 1.6 and 2.0 MPa, the cardiomyocyte injury (indicated by Evans blue stain) showed a significant increase relative to the control cells. At 2.0 MPa, Evans blue-stained cell counts also increased with increasing MP 115 dose from 10 to 50 µl/kg.

Kobayashi et al. (21) investigated the influence of DMP 115 on microvessels in the rat mesentery and myocardium. The interaction between 0.1 ml/kg DMP 115 and US exposure did not cause microvessel bleeding and endothelial cell injury. When the dose was increased to 1.0 ml/kg, there was evidence of capillary bleeding and increased endothelial cell injury. Microvessel bleeding was not observed under any conditions.

Other Non-Primate Mammals

[PubMed]

Maruyama et al. (22) showed that DMP 115 could provide contrast enhancement of the VX-2 tumor in rabbit livers. Margins of the liver tumor were well-defined at DMP 115 doses of 10 µl/kg (MI = 0.6) and 30 µl/kg (MI = 0.2).

Toledo et al. (19) studied the RT3DE technology (MI = 0.4-0.8) with DMP 115 (1.3 ml in 25 ml of saline and infused at 150-260 ml/h) in 5 pigs with partial coronary occlusion. Administration of DMP 115 and RT3DE imaging showed that coronary occlusion caused a 59 ± 26% decrease in the calculated peak contrast inflow rate (PCIR) in agreement with measurements by fluorescent microspheres.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Kitzman et al. (23) studied the efficacy and safety of DMP 115 in patients with suboptimal baseline LC echocardiographic images in a multicenter (17 sites), randomized, placebo-controlled, double-blind trial. Each patient received two i.v. doses of either 5 µl/kg (n = 85) or 10 µl/kg (n = 84) DMP 115 at 30 min apart. There was no clinically significant change in physical examination, vital signs, electrocardiographic tracings, or chemistry or hematology laboratory values. The adverse event rates were 18% compared with 14% in the placebo group (n = 42). Headache (5%) was the most frequent adverse event. Clinically useful contrast was recorded in 89% of patients compared with 0% of the placebo group. Improvement in endocardial border delineation was found in 91% of DMP 115 patients and in 12% of patients who received placebo.

Murthy et al. (10) investigated the real-time MCE (frame rates = 6-20 Hz; MI = 0.1-0.4) in 23 healthy volunteers. The DMP 115 doses ranged from 1,300 to 1,950 µl in 25-35 ml of normal saline and were given at an infusion rate of 4-6.5 ml/min. Real-time MCE appeared to give a more homogeneous opacification of the myocardium than that of triggered imaging. It was also possible to quantify flow reserve in normal healthy volunteers. Oraby et al. (24) used a newly developed US software, coherent contrast imaging (CCI), to perform real-time MCE in 42 men who had known or suspected coronary artery disease and adequate apical windows. They found that in this particular population of patients, it was feasible to use real-time CCI echocardiography to assess myocardial perfusion and LV wall motion. In 8 normal volunteers, Toledo et al. (19) used RT3DE imaging to show that adenosine increased PCIR to 198 ± 57% of baseline.

References

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Benko L.B. UnitedHealth snags Definity. Mod Healthc. 2004;34(49):8–9. [PubMed: 15624677]
2.
Rosenberg M.L., Carpenter A.P. Contrast material-enhanced abdominal US examinations with DMP 115 (DEFINITY) provides additional diagnostic information with potential for changes in patient management Acad Radiol 2002. 9Suppl 1S243–5. [PubMed: 12019880]
  • 3. Definity vial for (Perflutren Lipid Microsphere) injectable Suspension package insert. September 2004, Bristol-Myers Squibb Medical Imaging. p. 1-2.
  • 4.
    Morawski A.M., Lanza G.A., Wickline S.A. Targeted contrast agents for magnetic resonance imaging and ultrasound. Curr Opin Biotechnol. 2005;16(1):89–92. [PubMed: 15722020]
    5.
    Schutt E.G., Klein D.H., Mattrey R.M., Riess J.G. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew Chem Int Ed Engl. 2003;42(28):3218–35. [PubMed: 12876730]
  • 6. Swanson, D.P., Enhancement agents for ultrasound: Fundamentals, in Pharmaceuticals in Medical Imaging, D.P. Swanson, H.M. Chilton and J.H. Thrall, Editor. 1990, MacMillan Publishing Co., Inc.: New York. p. 682-687.
  • 7. Gobuty, A.H., Perspectives in ultrasound contrast agents, in Contrast media: Biologic effects and clinical application, Z. Parvez, R. Moncada and M. Sovak, Editor. 1987, CRC: Boca Raton, Florida. p. 145-155.
  • 8.
    Averkiou M., Powers J., Skyba D., Bruce M., Jensen S. Ultrasound contrast imaging research. Ultrasound Q. 2003;19(1):27–37. [PubMed: 12970614]
    9.
    Miller A.P., Nanda N.C. Contrast echocardiography: new agents. Ultrasound Med Biol. 2004;30(4):425–34. [PubMed: 15121243]
    10.
    Murthy T.H., Li P., Locvicchio E., Baisch C., Dairywala I., Armstrong W.F., Vannan M. Real-time myocardial blood flow imaging in normal human beings with the use of myocardial contrast echocardiography. J Am Soc Echocardiogr. 2001;14(7):698–705. [PubMed: 11447415]
    11.
    Riess J.G. Oxygen carriers ("blood substitutes")--raison d'etre, chemistry, and some physiology. Chem Rev. 2001;101(9):2797–920. [PubMed: 11749396]
    12.
    Riess J.G. Blood substitutes and other potential biomedical applications of fluorinated colloids. Journal of Fluorine Chemistry. 2002;114:119–126.
    13.
    Mattrey R.F., Trambert M.A., Brown J.J., Bruneton J.N., Young S.W., Schooley G.L. Results of the phase III trials with Imagent GI as an oral magnetic resonance contrast agent Invest Radiol 1991. 26Suppl 1S65–6. [PubMed: 1808151]
    14.
    Pashkevich D.S., Shelopin G.G., Mukhortov D.A., Petrov V.B., Alekseev Y.I., Asovich V.S. and Synthesis of perfluoroalkanes by high-temperature reaction of graphite with fluorine in a fluidized bed. Macromolecular chemistry and polymeric materials, 77(11): p. 1847-1853. 2004
    15.
    Blomley M., Claudon M., Cosgrove D. WFUMB Safety Symposium on Ultrasound Contrast Agents: clinical applications and safety concerns. Ultrasound Med Biol. 2007;33(2):180–6. [PubMed: 17254696]
    16.
    Riess J.G. Fluorous micro- and nanophases with a biochemical perspective. Tetrahedron. 2002;58:4113–4131.
    17.
    Moran C.M., Watson R.J., Fox K.A., McDicken W.N. In vitro acoustic characterisation of four intravenous ultrasonic contrast agents at 30 MHz. Ultrasound Med Biol. 2002;28(6):785–91. [PubMed: 12113791]
    18.
    Sboros V., Moran C.M., Pye S.D., McDicken W.N. The behaviour of individual contrast agent microbubbles. Ultrasound Med Biol. 2003;29(5):687–94. [PubMed: 12754068]
    19.
    Toledo E., Lang R.M., Collins K.A., Lammertin G., Williams U., Weinert L., Bolotin G., Coon P.D., Raman J., Jacobs L.D., Mor-Avi V. Imaging and quantification of myocardial perfusion using real-time three-dimensional echocardiography. J Am Coll Cardiol. 2006;47(1):146–54. [PubMed: 16386679]
    20.
    Miller D.L., Li P., Dou C., Gordon D., Edwards C.A., Armstrong W.F. Influence of contrast agent dose and ultrasound exposure on cardiomyocyte injury induced by myocardial contrast echocardiography in rats. Radiology. 2005;237(1):137–43. [PubMed: 16183929]
    21.
    Kobayashi N., Yasu T., Yamada S., Kudo N., Kuroki M., Miyatake K., Kawakami M., Saito M. Influence of contrast ultrasonography with perflutren lipid microspheres on microvessel injury. Circ J. 2003;67(7):630–6. [PubMed: 12845189]
    22.
    Maruyama H., Matsutani S., Saisho H., Kamiyama N., Yuki H., Miyata K. Grey-scale contrast enhancement in rabbit liver with DMP115 at different acoustic power levels. Ultrasound Med Biol. 2000;26(9):1429–38. [PubMed: 11179617]
    23.
    Kitzman D.W., Goldman M.E., Gillam L.D., Cohen J.L., Aurigemma G.P., Gottdiener J.S. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol. 2000;86(6):669–74. [PubMed: 10980221]
    24.
    Oraby M.A., Hays J., Maklady F.A., El-Hawary A.A., Yaneza L.O., Zabalgoitia M. Comparison of real-time coherent contrast imaging to dipyridamole thallium-201 single-photon emission computed tomography for assessment of myocardial perfusion and left ventricular wall motion. Am J Cardiol. 2002;90(5):449–54. [PubMed: 12208400]
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