UltraSound - Technology Information PortalWednesday, 23 May 2018



Ultrasound Contrast Agents

  • Historical Development
Magnetic Resonance Imaging Contrast Agents Open this link in a new window
Radiology Contrast Agents Open this link in a new window
History of Ultrasound Contrast Agents 

The earliest introduction of vascular ultrasound contrast agents (USCA) was by Gramiak and Shah in 1968, when they injected agitated saline into the ascending aorta and cardiac chambers during echocardiographic to opacify the left heart chamber. Strong echoes were produced within the heart, due to the acoustic mismatch between free air microbubbles in the saline and the surrounding blood.
The disadvantage of this microbubbles produced by agitation, was that the air quickly leak from the thin bubble shell into the blood, where it dissolved. In addition, the small bubbles that were capable of traversing the capillary bed did not survive long enough for imaging because the air quickly dissipated into the blood. Aside from agitated saline, also hydrogen peroxide, indocyanine green dye, and iodinated contrast has been tested. The commercial development of contrast agents began in the 1980s with greatest effort to the stabilization of small microbubbles.

The development generations by now:
point first generation USCA = non-transpulmonary vascular;;
point second generation USCA = transpulmonary vascular, with short half-life (less than 5 min);
point third generation USCA = transpulmonary vascular, with longer half-life (greater than 5 min).

To pass through the lung capillaries and enter into the systemic circulation, microspheres should be less than 10 µm in diameter. Air bubbles in that size range persist in solution for only a short time; too short for systemic vascular use.
The first developed agent was Echovist (1982), which enabled the enhancement of the right heart. The second generation of echogenic agents, sonicated 5% human albumin-containing air bubbles (Albunex), were capable of transpulmonary passage but often failed to produce adequate imaging of the left heart. Both Albunex and Levovist utilize air as the gas component of the microbubble.
In the 1990s newer developed agents with fluorocarbon gases and albumin, surfactant, lipid, or polymer shells have an increased persistence of the microspheres. This smaller, more stable microbubble agents, and improvements in ultrasound technology, have resulted in a wider range of application including myocardial perfusion.
See also First Generation USCA, Second Generation USCA, and Third Generation USCA.

• View the DATABASE results for 'History of Ultrasound Contrast Agents' (4).Open this link in a new window.

 Further Reading:
The First Long-Lasting Use of Echocardiography: A Result of a False AdvertisementOpen this link in a new window
2008   by imaging.onlinejacc.org    
  News & More:
The clinical applications of contrast echocardiography(.pdf)Open this link in a new window
2000   by cme.medscape.com     
First generation USCA 

The first generation ultrasound contrast agents (UCA/USCA) do not pass the pulmonary vascular bed, and are therefore limited to the venous system and the right heart cavities after intravenous injection.

• View the DATABASE results for 'First generation USCA' (5).Open this link in a new window.

Second Generation USCA 

The second generation ultrasound contrast agents (UCA/USCA) are both sufficiently small and stable to pass into the systemic circulation, and these contrast media enhance the Doppler signal in various arteries after intravenous injection. Second generation agents have a short live, the contrast effect is over in a few minutes.

• View the DATABASE results for 'Second Generation USCA' (5).Open this link in a new window.

Third Generation USCA 

The third generation ultrasound contrast agents (UCA/USCA) are more echogenic and stable, and are able to enhance the echogenicity of parenchyma on B-mode images. These microbubbles may thus show perfusion, even in such a difficult region as the myocardium.
See also History of Ultrasound Contrast Agents.

• View the DATABASE results for 'Third Generation USCA' (3).Open this link in a new window.

Drug Development and Approval Process (USA) 

Different stages of the drug development and approval process in the USA, lead from preclinical trials (testing in animals), first application in humans through limited and broad clinical tests, to postmarketing studies.

Years Test Population Purpose Success Rate
Preclinical Testing 3.5 Laboratory and animal studies Assess safety and biological activity 5,000 compounds evaluated
File IND at FDA
Phase I 1 20 to 80 healthy volunteers Determine safety and dosage 5 enter trials
Phase II 2 100 to 300 patient volunteers Evaluate effectiveness, look for side effects
Phase III 3 1000 to 3000 patient volunteers Verify effectiveness, monitor adverse reactions from long-term use
File NDA at FDA
FDA 2.5 Review process / Approval 1 approved
12 Total
Phase IV Additional Post marketing testing required by FDA

By Dale E. Wierenga, Ph.D. and C. Robert Eaton
Office of Research and Development
Pharmaceutical Manufacturers Association

'In reviewing this report, it is important to keep in mind the realities of the drug discovery and development process. The U.S. system of new drug approvals is perhaps the most rigorous in the world. On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment.'
See also Phase 1 2 3 4 Drug Trials, Food and Drug Administration, and European Medicines Agency.
  Microbubbles CA Intro top
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