Current Synthetic Blood Products

Contents
1.The Basics
2.Game On: First FDA Approved
3.The Major Players
4.Infinity and Beyond: The Future
Please click on images to be linked to their references. All images are referenced.
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Perfluorocarbon emulsions (PFCE) are one of the two major classes ofoxygen therapeutics currently on the market. They are composed ofliquid perfluorocarbonemulsified in water and salt. Due to the PFC‘s inability to remainmixed with aqueous solutions, they must be prepared as emulsions beforebeing used in patients. The PFCE particles are spherical, averagingabout .2 microns in diameter, with a perfluorocarbon core and a thinegg yolkphospholipids surfactant as a coating.
Inthe production, the PFC molecules are mixed with water, salts and thesurfactant (typically an egg yolk phospholipids in current PFCE‘s) viahigh pressure homogenization and sterilized with high temperaturesteam. The entire process takes 12-14 hours with close to a 100% yieldof product and can be done so at a large scale without much cost.
Dueto the synthetic nature of PFCE‘s, the product has a shelf life of 2years and minimizes the risk of infection or immunologic reactionresultingfrom a transfusion (i.e. mismatched blood type, mismatched Rh factor ordiseases such as HIV and Hepatitis B). In addition, PFCE‘s dissolveoxygen (unlike hemoglobin, which binds the molecule), which allow themto load/unload oxygen 2 times faster than hemoglobin, extract >90%of the transported oxygen and as evident in Oxygent™ (a current PFCEproduct), deliver the amount of oxygen of 1-2 units of red blood cellsin one unit of PFCE product (100-110 ml). About 4-12 hours afterinfusion, the PFCE particles are removed from the circulation vianormal respiration.
As with any medical product on themarket, a number of side effects have been associated with the use ofPFCE‘s. The side effects are mainly due to reticuloendothelial system(RES) macrophage phagocytosis of the PFCE particles and includeflu-like symptoms (fever, muscle aches, nausea and vomiting),hepatosplenomegaly,and a decrease in blood platelet count. Also, since the PFCE particlescan‘t be metabolized, it can take as many as 18-24 months to remove allof the particles.
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In1989, Fluosol ® , a PFCE produced by Green Cross Corp. of Osaka , Japan, became the first of its kind to receive FDA approval. It was approvedfor use in coronary balloon angioplasty procedures. Unfortunately,due to a number of problems with the product such as low PFC content(20%/voume) and the necessity for a labor-intensive preparation amongothers, Fluosol ® was discontinued in 1994.
CurrentPFCE products are referred to as second generation PFCE‘s and aremarketed as oxygen therapeutics for patients at risk of acute hypoxiaresulting from transient anemia, blood loss or ischemia. They usedifferent PFC‘s and surfactants than the previous products. The PFCEparticles travel in the plasma near the vessel walls and between RBC‘s.The largest plasma gaps between RBC‘s exist in the microcirculation soas a result, PFCE‘s provide the most benefit to smaller vessels. Also,when there are local areas of vasoconstriction or blockages of thevessels, some plasma can still pass through and deliver PFCE‘s/oxygento the tissues. Initially, they were created in order to avoid orreduce the need for blood transfusions in the treatment of traumapatients but as time went on, they began to be used in cardiovascular,orthopedic, urologic and other general surgeries.
The Major Players
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Alliance Pharmaceutical Corp.
AlliancePharmaceutical Corp., with the help of Johnson and Johnson, iscurrently working for FDA approval of Oxygent™. Oxygent™ is a secondgeneration PFCE with a median particle diameter of .16-.18 microns, anoptimal storage temperature of 2-8 °C, and a PFC content of 60%/voume.Data from numerous studies, including a European Phase III study of 492patients investigating the use of Oxygent™ in general surgery, showedthat the product reduced the need for transfused blood. While a PhaseIII trial involving CABG in the US was halted due to high stroke ratesin both the experimental and control groups, Alliance is hoping toinitiate further Phase III studies involving general surgery.
Alliance has also patented a procedure called Augmented Acute Normovolemic Hemodilution (Augmented-ANH), which is a technique that will further decrease theneed for blood transfusions in moderate and high blood loss surgicalprocedures. Immediately prior to surgery, several pints of blood areremoved from the patient and Oxygent™ is used to replace theoxygen-carrying capacity of the missingblood and following surgery, the removed blood is reinfused.
Recently,the European Agency for the Evaluation of Medical Products (EMEA)recommended that Alliance pursue an indication for Oxygent™ that doesnot require direct comparison to allogeneic blood transfusions. Sincethe incidence of serious adverse side effects associated with bloodtransfusions are so low, it would be difficult to show that Oxygent™ issafe or safer than allogeneic blood. Also recently, Alliance and itssubsidiary PFC Therapeutics, LLC began working with Double-CranePharmaceutical CO., Ltd. And LEO Pharma A/S to develop and marketOxygent™ in The People‘s Republic of China (Double-Crane), Europe andCanada (LEO).
Synthetic Blood International, Inc.
SyntheticBlood International (SYBD) is currently marketing its product Oxycyte™.Oxycyte is a second-generation PFCE similar to Oxygent™ with a meanparticle diameter of .19 microns, PFC content of 60%/volume and atypical pH of 7.1. When compared to other PFC products, data fromscreening animal studies is providing a good safety profile forOxycyte™.
On April 18, 2005 , SYBD announced that thefirst two of sixty patients were enrolled in a Phase II trial forOxycyte™ in the prevention of tissue hypoxia in hip revision surgery.Currently, there are four US clinical sites involved and SYBD hopes toeventually have six. Future Phase II trials will involve the use ofOxycyte™ in CABG, and heart valve replacement surgery, among others.
Sanguine Corp.
SanguineCorp. is working towards the FDA approval of the second-generation PFCEPHER-02 that was designed to overcome the shortcomings of itspredecessor: Fluosol ®. On April 25, 2005 , Sanguine Corp. announcedthat it is currently working to determine a final FDA indication forPHER-02 so that any further research and and clinical trials are gearedtowards the fastest path to FDA approval.
The CEO andPresident of Sanguine, Dr. Thomas C. Drees, Ph. D., was quoted assaying, “With the results of these animal trials coming in, we findourselves in a very good position … We have found very large markets,which should have a very direct FDA approval path.”(Sanguine Corp.)
Perftoran
TheRussian based company Perftoran is currently producing Perftoran, whichis not a second-generation PFCE like the previous products but rather,it is an improved first-generation PFCE. It was registered in Russia in1996 and is similar to Fluosol ® except that it uses a differentemulsifier which contributes to its lower incidence of side-effects.The product particles are .07 microns in diameter, allowing them toevade RES macrophages to an extent and remain in the vasculature longerwith fewer side-effects. It has a PFC content of 10%/volume, can bestored at 3 years at -4 ° C - -18° C and two weeks at 4° C. Within twoweeks before infusion, Perftoran must be thawed at room temperature andsubsequently stored at 4° C. Also, it can be thawed and refrozen up tofive times.
By the end of 2000, more than 2000 patientshad participated in clinical studies of Perftoran, 37% of whichinvolved anemia, hemoraghic and traumatic shock, 19% involvedpolytrauma and fat embolism, 13% involved ischemic brain edema andtransplantation, and 15% involved acute ischemia.
To Infinity and Beyond…
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WhilePFCE‘s may never oust the practice of blood transfusion or be approvedas a “blood substitute”, they do hold a great deal of potential forother applications. PFCE‘s could be incorporated into cardioplegicsolutions used in open heart surgery.Suchan application has the potential to benefit cardiac oxygenation, tissuemetabolic status and quicken recovery following the stoppage of theheart. PFCE‘s could also be used in supplying devascularized organswith oxygen prior to transplantation. Along those
same lines,they could be used to perfuse the myocardium or brain tissue in heartattacks and strokes, oxygenating obstructed regions due to blockage andhopefully improving survival and recovery.
Anotherpossible area of application is in cancer therapy. PFCE‘s couldincrease the oxygenation of tumors, consequently benefiting radiationand/or chemotherapy in cancer treatment. Chemotherapeutic drugs couldbeadded to the PFCE and carried along to the site of the cancer. Also,local application of toxic doses of PFCE‘s (namely PHER-O2) resulted inthe necrosis of cancer cells. This is especially promising in thetreatment of cancers of the head and neck regions which are currentlydifficult to treat.
Other possible applications includethe treatment of fungal/bacterial skin and GI tract infections, oxygendeficient conditions (i.e. carbon monoxide poisoning), Alzheimer‘sDisease and medical imaging.
The image to the rightis a picture taken of a mouse completely submerged in liquid perfluorocarbon and still breathing!

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Brown University
(Organ Replacement 108, Prof. Lysaght)