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From POINT Biomedical Corp
BiSphere™ is a technology for drug delivery applications by ultrasound. BiSpheres™ consists of microparticles comprising a shell of an outer layer of a biologically compatible material and an inner layer of biodegradable polymer. The core of the microbubbles contains a filling gas, liquid, or solid for use in drug delivery or as a contrast agent for ultrasonic contrast imaging. The contrast agent particles are capable of passing through the capillary systems of a subject. The drug-loaded biSpheres™ would be administered intravenously and freely circulate throughout the body, while the drug encapsulated within would remain biologically unavailable. The drug would only be released when the biSpheres become flooded when passing through an externally directed ultrasound field.
The use of biSpheres™ to transport agents to specific sites within the body is expected to substantially increase local efficacy while decreasing systemic side effects or adverse reactions. The biSpheres™ may also serve to protect labile agents from metabolism or degradation. The noninvasive release of a protected, encapsulated agent can be controlled by ultrasound imaging to a depth of 20-30 cm from the skin surface.
The flexibility in size control in the biSphere™ technology has enabled the construction of submicron ultrasound contrast agents suitable for lymphatic imaging, with a diameter in the submicron range. This agent, while much smaller in size than CardioSphere®, is based on the BiSphere configuration: a shell within a shell enclosing a gas. The inner layer, made from a biodegradable polymer, provides the physical structure and controls the acoustic response. The outer layer functions as the biological interface. Each of these layers has been independently tailored to fulfill the specific requirements for lymphatic imaging.

The company is a member of the Bracco Group, a highly innovative health care group and world leader in global integrated solutions for the diagnostic imaging field. The Bracco Group is headquartered in Milan, Italy. Its North American operations consist of Bracco Diagnostics and Bracco Research USA, both located in Princeton, New Jersey. Bracco Diagnostics is one of the fastest growing developers and marketers of diagnostic pharmaceuticals in North America, with products for various imaging applications, including Isovue® (iopamidol) X-ray contrast agent, ProHance®, (gadoteridol), MRI contrast agent, and nuclear medicine products.
Gadoteridol has been available in Europe and the USA for several years. Holder of the Marketing Authorization: Bracco International B.V. - Strawinskylaan 3051 - 1077 ZX Amsterdam The Netherlands. (Contact: Kirk Deeter, Phone: +NL-303-838-8708)

The Bracco Group is the world's leading provider of global diagnostic imaging solutions, with net sales of more than 1 billion euro, of which more than 64% from international sales; it has operations in 115 countries and about 3,500 employees, of whom more than 600 work in R&D. Bracco invests around 15% of its turnover in R&D and has a portfolio of 1,500 patents worldwide. The Bracco Group deploys an integrated approach to diagnostic imaging, with an offer that encompasses contrast media, its core business where it is one of the world's top players, biomedical equipment from Esaote, one of the world's primary producers of magnetic resonance and ultrasonographic medical equipment, contrast media delivery systems from Acist Medical Systems, a top US company in advanced contrast media injection systems, and medical application software from EBIT-AET and Singapore's Volume Interactions, the leading developer of advanced medical software. Bracco has formed a high-level international research network, whose three centers in Milan, Geneva and Princeton study and develop products for the latest-generation diagnostic techniques, from X-rays and computerized axial tomography to magnetic resonance and echo contrast.

Ultrasound Contrast Agents:

(CHI) Contrast harmonic imaging is an ultrasound technique to improve the measurement of blood perfusion or capillary blood flow. Based on the nonlinear properties of contrast agents, CHI transmits at the fundamental frequency but receives at the second harmonic. Contrast enhanced echo signals contain significant energy components at higher harmonics (bubbles acts as harmonic oscillators), while tissue echoes do not. Caused by that contrast signal can be separated from tissue echoes by the characteristic signal.
In combination with the pulse inversion technique, CHI promises very high contrast agent sensitivity with high spatial resolution.

See also Ultrasound Contrast Agent Safety and Hemoglobin.

Echogenicity is the ability of a medium to create an echo, for example to return a signal when tissue is in the path of the sound beam. The ultrasound echogenicity is dependent on characteristics of tissues or contrast agents and is measured by calculating the backscattering and transmission coefficients as a function of frequency.
The fundamental parameters that determine echogenicity are density and compressibility. Blood is two to three orders of magnitude less echogenic than tissue due to the relatively small impedance differences between red blood cells and plasma. The tissue echogenicity can be increased by ultrasound contrast agents. Encapsulated microbubbles are highly echogenic due to differences in their compressibility and density, compared to tissue or plasma.
Microbubbles are 10,000 times more compressible than red blood cells. The compressibility of air is 7.65 x 10−6 m2/N, in comparison with 4.5 x 10-11 m2/N for water (on the same order of magnitude as tissue and plasma). This impedance mismatch results in a very high echogenicity. An echo from an individual contrast agent can be detected by a clinical ultrasound system sensitive to a volume on the order of 0.004 pl.

See also Isoechogenic, Retrolenticular Afterglow, and Sonographic Features.

See also Imagent®.
June 19, 2003
Alliance Pharmaceutical Corporation and Photogen Technologies, Inc. announced that they have closed the previously announced transaction whereby Photogen has acquired all of the assets of Alliance related to medical imaging, including all manufacturing and marketing rights to Imagent (formerly Imavist). Terms of the transaction were not disclosed.

June 03, 2002
Alliance Pharmaceutical Corp. announced that its ultrasound imaging agent, Imagent (perflexane lipid microspheres), has been approved for marketing by the U.S. Food and Drug Administration. The product will be marketed by Alliance in partnership with Cardinal Health, Inc., a provider of products and services to the healthcare industry, and inChord Communications, Inc., an independent healthcare communications company.

March 01, 2002
'Alliance Pharmaceutical Corp. announced that it has entered into a partnership with Bayer Schering Pharma AG, Germany and Cardinal Health Inc. for the marketing of Imavist (perflexane lipid microspheres), an ultrasound contrast agent. Schering licensed worldwide marketing rights for Imavist from Alliance in September 1997. The companies have agreed to modify this agreement to allow Alliance to increase its participation in the marketing of the product. Under the terms of the modified agreement, Alliance will have exclusive marketing rights to Imavist for cardiology indications in the U.S. for five years, and Schering will receive a royalty on product sales. Schering retains marketing rights for other indications in the U.S. and all indications in the rest of the world, subject to Alliance's option to obtain additional indications and territories. Under certain circumstances, Schering would co-market the product at the end of five years. Concurrently, Alliance has entered into a five-year exclusive agreement with Cardinal Health Inc., a provider of products and services to the health-care industry, to assist in the marketing of Imavist.'

October 08, 2001
'Alliance Pharmaceutical Corp. announced a clinical study to take place at Thomas Jefferson University Hospital, Philadelphia, using Alliance's Imavist (AF0150) contrast agent with ultrasound imaging to improve detection of prostate cancer. The study, which will involve 300 adult men with suspected prostate cancer, is being funded by the U.S. Department of Defense under a competitive grant awarded to Thomas Jefferson University for investigators at Jefferson's Prostate Center. Imavist is being developed jointly by Alliance and Bayer Schering Pharma AG Germany, and is awaiting final approval from the U.S. Food and Drug Administration.'

August 21, 2000
Alliance Pharmaceutical Corp. announced that it has received a letter from the U.S. Food and Drug Administration (FDA) stating that the FDA has completed its review of the New Drug Application (NDA) for Imagent (AF0150), and found it to be approvable. Imagent, an ultrasound contrast agent, is being developed jointly by Alliance and Bayer Schering Pharma AG, Germany

Notes:
The manufacturer is pursuing additional radiology indications such as ultrasound imaging of the prostate and liver, and clinical trials are currently being conducted to evaluate Imagent in conjunction with ultrasound imaging for use in the detection of prostate cancer. During the course of its development, the brand name for this product has changed from Imagent to Imavist back to Imagent. Initially reported on by the manufacturer as Imagent and then, between August 2000 and March 2002, as 'Imavist (formerly Imagent).' The manufacturer's 06/03/02 press release announcing FDA approval refers to the product as 'Imagent (formerly Imavist),' and the approval notice and monograph posted at the FDA site refers to the product as Imagent. Jointly developed by Alliance Pharmaceutical Corp and Bayer Schering Pharma AG, (Germany). Source: PR Newswire - 10/10/96, 03/31/98, 10/13/99, 03/13/01, 10/08/01; FDA approvals - 05/31/02; Alliance Pharmaceutical press release - 06/03/02.