In June 2007 Tyco International Ltd. completed the separation of its healthcare business, which is named Covidien. Mallinckrodt, Inc. is now part of Covidien Ltd. The company makes and distributes products for respiratory care; bulk and dosage pharmaceuticals, primarily for pain relief and addiction therapy; and imaging agents for magnetic resonance, ultrasound, x-ray, and nuclear medicine applications. With worldwide manufacturing and distribution facilities and sales offices, Mallinckrodt, Inc. sells its products worldwide.
Albunex was one of the first marketed ultrasound contrast agents. Currently, Mallinckrodt discontinued the manufacturing and development of ultrasound contrast agents.

Ultrasound Contrast Agents:

The definition of imaging is the visual representation of an object. Medical imaging is a broad term that encompasses various imaging modalities and techniques used in the field of medicine to visualize and study the body's anatomy and physiology. It includes both diagnostic and non-diagnostic imaging procedures, where diagnostic imaging specifically refers to the subset of medical imaging techniques that are primarily focused on diagnosing diseases or conditions. Medical imaging techniques are employed to obtain images or visual representations of the internal organs, tissues, and structures, aiding in the diagnosis, treatment, and monitoring of medical conditions.
The field of medical imaging has significantly evolved since the discovery of X-rays by Konrad Roentgen in 1896. Initially, radiological imaging involved focusing X-rays on the body and capturing the images on a single piece of film within a specialized cassette. Subsequent advancements introduced the use of fluorescent screens and special glasses for real-time visualization of X-ray images.
A significant breakthrough came with the application of contrast agents, enhancing image contrast and improving organ visualization. In the 1950s, nuclear medicine studies utilizing gamma cameras demonstrated the uptake of low-level radioactive chemicals in organs, enabling the observation of biological processes in vivo. Currently, positron emission tomography (PET) and single photon emission computed tomography (SPECT) technologies play pivotal roles in clinical research and the diagnosis of biochemical and physiological processes. Additionally, the advent of the x-ray image intensifier in 1955 facilitated the capture and display of x-ray movies.
In the 1960s, diagnostic imaging incorporated the principles of sonar, using ultrasonic waves generated by a quartz crystal. These waves, reflecting at the interfaces between different tissues, were received by ultrasound machines and translated into images through computer algorithms and reconstruction software. Ultrasound (ultrasonography) has become an indispensable diagnostic tool across various medical specialties, with immense potential for further advancements such as targeted contrast imaging, real-time 3D or 4D ultrasound, and molecular imaging. The first use of ultrasound contrast agents (USCA) dates back to 1968.
Digital imaging techniques were introduced in the 1970s, revolutionizing conventional fluoroscopic image intensifiers. Godfrey Hounsfield's pioneering work led to the development of the first computed tomography (CT) scanner. Digital images are now electronic snapshots represented as grids of dots or pixels. X-ray CT brought about a breakthrough in medical imaging by providing cross-sectional images of the human body with high contrast between different types of soft tissue. These advancements were made possible by analog-to-digital converters and computers. The introduction of multislice spiral CT technology dramatically expanded the clinical applications of CT scans.
The first magnetic resonance imaging (MRI) devices were tested on clinical patients in 1980. With technological improvements, such as higher field strength, more open MRI magnets, faster gradient systems, and novel data-acquisition techniques, MRI has emerged as a real-time interactive imaging modality capable of providing detailed structural and functional information of the body.
Today, imaging in medicine offers a wide range of modalities, including:

These imaging modalities have become integral components of modern healthcare. With the rapid advancement of digital imaging, efficient management has become important, leading to the expansion of radiology information systems (RIS) and the adoption of Picture Archiving and Communication Systems (PACS) for digital image archiving. In telemedicine, real-time transmission of all medical image modalities from MRI to X-ray, CT and ultrasound has become the standard. The field of medical imaging continues to evolve, promising further innovations and advancements in the future, ultimately contributing to improved patient care and diagnostics.

See also History of Ultrasound Contrast Agents, and History of Ultrasound.

Standard scanners allow visualizing microbubbles on conventional gray scale imaging in large vascular spaces. In the periphery, more sensitive techniques such as Doppler or non-linear gray scale modes must be used because of the dilution of the microbubbles in the blood pool. Harmonic power Doppler (HPD) is one of the most sensitive techniques for detecting ultrasound contrast agents.
Commonly microbubbles are encapsulated or otherwise stabilized to prolong their lifetime after injection. These bubbles can be altered by exposure to ultrasound pulses. Depending on the contrast agent and the insonating pulse, the changes include deformation or breakage of the encapsulating or stabilizing material, generation of free gas bubbles, reshaping or resizing of gas volumes.
High acoustic pressure amplitudes and long pulses increase the changes. However, safety considerations limit the pressure amplitude and long pulses decrease spatial resolution. In addition, lowering the pulse frequency increases destruction of contrast bubbles. However, at low insonation power levels, contrast agent particles resist insonation without detectable changes. Newer agents are more reflective and will usually allow gray scale imaging to be used with the advantages of better spatial resolution, fewer artifacts and faster frame rates.

Feasible imaging methods with advantages in specific acoustic microbubble properties:
Resonating microbubbles emit harmonic signals at double their resonance frequency. If a scanner is modified to select only these harmonic signals, this non-linear mode produces a clear image or trace. The effect depends on the fact that it is easier to expand a bubble than to compress it so that it responds asymmetrically to a symmetrical ultrasound wave. A special array design allows to perform third or fourth harmonic imaging. This probe type is called a dual frequency phased array transducer.

See also Bubble Specific Imaging.

From GE Healthcare;;
Optison is the first 'second generation USCA' marketed in the US.
Ultrasound contrast agents used during an ultrasound imaging procedure, enable more accurate diagnosis of the patient's heart condition. The application of Optison allows to image the endocardial borders of the heart, to see cardiac wall motion abnormalities and to guide the selection and monitoring of treatment.
Optison represents a class of microbubbles with a shell formed by sonicating a solution of capsules filled with a perfluoropropane gas. The high molecular weight slows microbubble dissolution and prolongs the enhancement for several minutes. The human albumin-stabilized cavitation bubbles have a surface tension of 0.9 N/m and a surface dilatational viscosity 0.08 msP.

'August 06, 2001 Molecular Biosystems Inc., a subsidiary of Alliance Pharmaceutical Corp, announced the amendment of the Optison Product Rights Agreement (OPRA) dated May 9, 2000 with Mallinckrodt Inc, a unit of Tyco Healthcare. Optison, an intravenous ultrasound contrast agent, was developed by MBI and is being marketed by Mallinckrodt in the U.S. and Europe. Under the amended agreement, MBI will receive an immediate cash payment plus additional unspecified royalties for a two-year period. The amendment of OPRA coincides with an announcement by Nycomed Amersham Imaging that Nycomed and Mallinckrodt will terminate their joint commercialization and development agreement for ultrasound contrast agents, including Optison, effective Dec. 31, 2001. Effective Jan. 1, 2002, all selling and marketing activities will be resumed solely by Nycomed Amersham.'

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From Acusphere Inc
AI-700 (trade name Imagify™) is an US contrast agent, usable for myocardial perfusion undergoing regulatory FDA approval. The synthetic polymers used in AI-700 (perflubutane polymer microspheres) do not break during the ultrasound imaging procedure. The used perfluorocarbon filling gas is less soluble in water and therefore has the propensity to stay inside the contrast agent particles. As a result, a higher concentration of gas is delivered to the myocardium over a longer period of time, thereby enabling AI-700 to target the broader application of myocardial perfusion assessment.
Imagify is a dry powder consisting of small, porous microparticles filled with perfluoropropane. These microparticles are made of a synthetic biodegradable polymer, called poly (D, L-lactide co-glycolide), or PLGA, that has been used in other drug delivery systems approved by the FDA.
The composition and structure of the phospholipid containing microparticles and the properties of the perfluorocarbon gas slow the rate at which the gas dissolves and prevent the microparticles from being quickly broken down. The powder is to suspend in sterile water and injected by a single intravenous injection prior to ultrasound imaging.

In 2009, Acusphere Inc received feedback from the Food and Drug Administration (FDA) to their New Drug Application (NDA) stating that another clinical trial would be required for U.S. approval, this one demonstrating that Imagify with ultrasound is superior to ultrasound without Imagify.
In June 2004, Acusphere entered into a Collaboration, License and Supply Agreement with Nycomed Danmark APS for the European development and marketing rights to Acusphere's lead product candidate AI-700.
Acusphere's focus will be on preparing the Marketing Authorization Application (MAA) for filing in Q4 2010, building upon the work that the previous partner, Nycomed, had done, in concert with the NDA.


In 2008 the FDA panel rejected the regulatory application for AI-700 (Imagify™) because of safety concerns.