Current Synthetic Blood Products

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.

The Basics

Perfluorocarbon emulsions (PFCE) are one of the two major classes of oxygen therapeutics currently on the market. They are composed of liquid perfluorocarbon emulsified in water and salt. Due to the PFC's inability to remain mixed with aqueous solutions, they must be prepared as emulsions before being used in patients. The PFCE particles are spherical, averaging about .2 microns in diameter, with a perfluorocarbon core and a thin egg yolk phospholipids surfactant as a coating.

In the production, the PFC molecules are mixed with water, salts and the surfactant (typically an egg yolk phospholipids in current PFCE's) via high pressure homogenization and sterilized with high temperature steam. The entire process takes 12-14 hours with close to a 100% yield of product and can be done so at a large scale without much cost.

Due to the synthetic nature of PFCE's, the product has a shelf life of 2 years and minimizes the risk of infection or immunologic reaction resulting from a transfusion (i.e. mismatched blood type, mismatched Rh factor or diseases such as HIV and Hepatitis B). In addition, PFCE's dissolve oxygen (unlike hemoglobin, which binds the molecule), which allow them to load/unload oxygen 2 times faster than hemoglobin, extract >90% of the transported oxygen and as evident in Oxygent™ (a current PFCE product), deliver the amount of oxygen of 1-2 units of red blood cells in one unit of PFCE product (100-110 ml). About 4-12 hours after infusion, the PFCE particles are removed from the circulation via normal respiration.

As with any medical product on the market, a number of side effects have been associated with the use of PFCE's. The side effects are mainly due to reticuloendothelial system (RES) macrophage phagocytosis of the PFCE particles and include flu-like symptoms (fever, muscle aches, nausea and vomiting), hepatosplenomegaly, and a decrease in blood platelet count. Also, since the PFCE particles can't be metabolized, it can take as many as 18-24 months to remove all of the particles.

Game On

(top)

In 1989, Fluosol ® , a PFCE produced by Green Cross Corp. of Osaka , Japan , became the first of its kind to receive FDA approval. It was approved for 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 among others, Fluosol ® was discontinued in 1994.

Current PFCE products are referred to as second generation PFCE's and are marketed as oxygen therapeutics for patients at risk of acute hypoxia resulting from transient anemia, blood loss or ischemia. They use different PFC's and surfactants than the previous products. The PFCE particles travel in the plasma near the vessel walls and between RBC's. The largest plasma gaps between RBC's exist in the microcirculation so as a result, PFCE's provide the most benefit to smaller vessels. Also, when there are local areas of vasoconstriction or blockages of the vessels, some plasma can still pass through and deliver PFCE's/oxygen to the tissues. Initially, they were created in order to avoid or reduce the need for blood transfusions in the treatment of trauma patients but as time went on, they began to be used in cardiovascular, orthopedic, urologic and other general surgeries.

The Major Players

(top)

Alliance Pharmaceutical Corp.

Alliance Pharmaceutical Corp., with the help of Johnson and Johnson, is currently working for FDA approval of Oxygent™. Oxygent™ is a second generation PFCE with a median particle diameter of .16-.18 microns, an optimal storage temperature of 2-8 °C, and a PFC content of 60%/voume. Data from numerous studies, including a European Phase III study of 492 patients investigating the use of Oxygent™ in general surgery, showed that the product reduced the need for transfused blood. While a Phase III trial involving CABG in the US was halted due to high stroke rates in both the experimental and control groups, Alliance is hoping to initiate 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 the need for blood transfusions in moderate and high blood loss surgical procedures. Immediately prior to surgery, several pints of blood are removed from the patient and Oxygent™ is used to replace the oxygen-carrying capacity of the missing blood 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 does not require direct comparison to allogeneic blood transfusions. Since the incidence of serious adverse side effects associated with blood transfusions are so low, it would be difficult to show that Oxygent™ is safe or safer than allogeneic blood. Also recently, Alliance and its subsidiary PFC Therapeutics, LLC began working with Double-Crane Pharmaceutical CO., Ltd. And LEO Pharma A/S to develop and market Oxygent™ in The People's Republic of China (Double-Crane), Europe and Canada (LEO).

Synthetic Blood International, Inc.

Synthetic Blood International (SYBD) is currently marketing its product Oxycyte™. Oxycyte is a second-generation PFCE similar to Oxygent™ with a mean particle diameter of .19 microns, PFC content of 60%/volume and a typical pH of 7.1. When compared to other PFC products, data from screening animal studies is providing a good safety profile for Oxycyte™.

On April 18, 2005 , SYBD announced that the first two of sixty patients were enrolled in a Phase II trial for Oxycyte™ in the prevention of tissue hypoxia in hip revision surgery. Currently, there are four US clinical sites involved and SYBD hopes to eventually have six. Future Phase II trials will involve the use of Oxycyte™ in CABG, and heart valve replacement surgery, among others.

Sanguine Corp.

Sanguine Corp. is working towards the FDA approval of the second-generation PFCE PHER-02 that was designed to overcome the shortcomings of its predecessor: Fluosol ®. On April 25, 2005 , Sanguine Corp. announced that it is currently working to determine a final FDA indication for PHER-02 so that any further research and and clinical trials are geared towards the fastest path to FDA approval.

The CEO and President of Sanguine, Dr. Thomas C. Drees, Ph. D., was quoted as saying, “With the results of these animal trials coming in, we find ourselves in a very good position … We have found very large markets, which should have a very direct FDA approval path.”(Sanguine Corp.)

Perftoran

The Russian based company Perftoran is currently producing Perftoran, which is not a second-generation PFCE like the previous products but rather, it is an improved first-generation PFCE. It was registered in Russia in 1996 and is similar to Fluosol ® except that it uses a different emulsifier which contributes to its lower incidence of side-effects. The product particles are .07 microns in diameter, allowing them to evade RES macrophages to an extent and remain in the vasculature longer with fewer side-effects. It has a PFC content of 10%/volume, can be stored at 3 years at -4 ° C - -18° C and two weeks at 4° C. Within two weeks before infusion, Perftoran must be thawed at room temperature and subsequently stored at 4° C. Also, it can be thawed and refrozen up to five times.

By the end of 2000, more than 2000 patients had participated in clinical studies of Perftoran, 37% of which involved anemia, hemoraghic and traumatic shock, 19% involved polytrauma and fat embolism, 13% involved ischemic brain edema and transplantation, and 15% involved acute ischemia.

To Infinity and Beyond…

(top)

While PFCE's may never oust the practice of blood transfusion or be approved as a “blood substitute”, they do hold a great deal of potential for other applications. PFCE's could be incorporated into cardioplegic solutions used in open heart surgery. Such an application has the potential to benefit cardiac oxygenation, tissue metabolic status and quicken recovery following the stoppage of the heart. PFCE's could also be used in supplying devascularized organs with oxygen prior to transplantation. Along those
same lines, they could be used to perfuse the myocardium or brain tissue in heart attacks and strokes, oxygenating obstructed regions due to blockage and hopefully improving survival and recovery.

Another possible area of application is in cancer therapy. PFCE's could increase the oxygenation of tumors, consequently benefiting radiation and/or chemotherapy in cancer treatment. Chemotherapeutic drugs could beadded 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 in the necrosis of cancer cells. This is especially promising in the treatment of cancers of the head and neck regions which are currently difficult to treat.

Other possible applications include the treatment of fungal/bacterial skin and GI tract infections, oxygen deficient conditions (i.e. carbon monoxide poisoning), Alzheimer's Disease and medical imaging.

The image to the right is a picture taken of a mouse completely submerged in liquid perfluorocarbon and still breathing!


	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. The Basics (top) Perfluorocarbon emulsions (PFCE) are one of the two major classes of oxygen therapeutics currently on the market. They are composed of liquid perfluorocarbon emulsified in water and salt. Due to the PFC's inability to remain mixed with aqueous solutions, they must be prepared as emulsions before being used in patients. The PFCE particles are spherical, averaging about .2 microns in diameter, with a perfluorocarbon core and a thin egg yolk phospholipids surfactant as a coating. In the production, the PFC molecules are mixed with water, salts and the surfactant (typically an egg yolk phospholipids in current PFCE's) via high pressure homogenization and sterilized with high temperature steam. The entire process takes 12-14 hours with close to a 100% yield of product and can be done so at a large scale without much cost. Due to the synthetic nature of PFCE's, the product has a shelf life of 2 years and minimizes the risk of infection or immunologic reaction resulting from a transfusion (i.e. mismatched blood type, mismatched Rh factor or diseases such as HIV and Hepatitis B). In addition, PFCE's dissolve oxygen (unlike hemoglobin, which binds the molecule), which allow them to load/unload oxygen 2 times faster than hemoglobin, extract >90% of the transported oxygen and as evident in Oxygent™ (a current PFCE product), deliver the amount of oxygen of 1-2 units of red blood cells in one unit of PFCE product (100-110 ml). About 4-12 hours after infusion, the PFCE particles are removed from the circulation via normal respiration. As with any medical product on the market, a number of side effects have been associated with the use of PFCE's. The side effects are mainly due to reticuloendothelial system (RES) macrophage phagocytosis of the PFCE particles and include flu-like symptoms (fever, muscle aches, nausea and vomiting), hepatosplenomegaly, and a decrease in blood platelet count. Also, since the PFCE particles can't be metabolized, it can take as many as 18-24 months to remove all of the particles. Game On (top) In 1989, Fluosol ® , a PFCE produced by Green Cross Corp. of Osaka , Japan , became the first of its kind to receive FDA approval. It was approved for 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 among others, Fluosol ® was discontinued in 1994. Current PFCE products are referred to as second generation PFCE's and are marketed as oxygen therapeutics for patients at risk of acute hypoxia resulting from transient anemia, blood loss or ischemia. They use different PFC's and surfactants than the previous products. The PFCE particles travel in the plasma near the vessel walls and between RBC's. The largest plasma gaps between RBC's exist in the microcirculation so as a result, PFCE's provide the most benefit to smaller vessels. Also, when there are local areas of vasoconstriction or blockages of the vessels, some plasma can still pass through and deliver PFCE's/oxygen to the tissues. Initially, they were created in order to avoid or reduce the need for blood transfusions in the treatment of trauma patients but as time went on, they began to be used in cardiovascular, orthopedic, urologic and other general surgeries. The Major Players (top) Alliance Pharmaceutical Corp. Alliance Pharmaceutical Corp., with the help of Johnson and Johnson, is currently working for FDA approval of Oxygent™. Oxygent™ is a second generation PFCE with a median particle diameter of .16-.18 microns, an optimal storage temperature of 2-8 °C, and a PFC content of 60%/voume. Data from numerous studies, including a European Phase III study of 492 patients investigating the use of Oxygent™ in general surgery, showed that the product reduced the need for transfused blood. While a Phase III trial involving CABG in the US was halted due to high stroke rates in both the experimental and control groups, Alliance is hoping to initiate 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 the need for blood transfusions in moderate and high blood loss surgical procedures. Immediately prior to surgery, several pints of blood are removed from the patient and Oxygent™ is used to replace the oxygen-carrying capacity of the missing blood 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 does not require direct comparison to allogeneic blood transfusions. Since the incidence of serious adverse side effects associated with blood transfusions are so low, it would be difficult to show that Oxygent™ is safe or safer than allogeneic blood. Also recently, Alliance and its subsidiary PFC Therapeutics, LLC began working with Double-Crane Pharmaceutical CO., Ltd. And LEO Pharma A/S to develop and market Oxygent™ in The People's Republic of China (Double-Crane), Europe and Canada (LEO). Synthetic Blood International, Inc. Synthetic Blood International (SYBD) is currently marketing its product Oxycyte™. Oxycyte is a second-generation PFCE similar to Oxygent™ with a mean particle diameter of .19 microns, PFC content of 60%/volume and a typical pH of 7.1. When compared to other PFC products, data from screening animal studies is providing a good safety profile for Oxycyte™. On April 18, 2005 , SYBD announced that the first two of sixty patients were enrolled in a Phase II trial for Oxycyte™ in the prevention of tissue hypoxia in hip revision surgery. Currently, there are four US clinical sites involved and SYBD hopes to eventually have six. Future Phase II trials will involve the use of Oxycyte™ in CABG, and heart valve replacement surgery, among others. Sanguine Corp. Sanguine Corp. is working towards the FDA approval of the second-generation PFCE PHER-02 that was designed to overcome the shortcomings of its predecessor: Fluosol ®. On April 25, 2005 , Sanguine Corp. announced that it is currently working to determine a final FDA indication for PHER-02 so that any further research and and clinical trials are geared towards the fastest path to FDA approval. The CEO and President of Sanguine, Dr. Thomas C. Drees, Ph. D., was quoted as saying, “With the results of these animal trials coming in, we find ourselves in a very good position … We have found very large markets, which should have a very direct FDA approval path.”(Sanguine Corp.) Perftoran The Russian based company Perftoran is currently producing Perftoran, which is not a second-generation PFCE like the previous products but rather, it is an improved first-generation PFCE. It was registered in Russia in 1996 and is similar to Fluosol ® except that it uses a different emulsifier which contributes to its lower incidence of side-effects. The product particles are .07 microns in diameter, allowing them to evade RES macrophages to an extent and remain in the vasculature longer with fewer side-effects. It has a PFC content of 10%/volume, can be stored at 3 years at -4 ° C - -18° C and two weeks at 4° C. Within two weeks before infusion, Perftoran must be thawed at room temperature and subsequently stored at 4° C. Also, it can be thawed and refrozen up to five times. By the end of 2000, more than 2000 patients had participated in clinical studies of Perftoran, 37% of which involved anemia, hemoraghic and traumatic shock, 19% involved polytrauma and fat embolism, 13% involved ischemic brain edema and transplantation, and 15% involved acute ischemia. To Infinity and Beyond… (top) While PFCE's may never oust the practice of blood transfusion or be approved as a “blood substitute”, they do hold a great deal of potential for other applications. PFCE's could be incorporated into cardioplegic solutions used in open heart surgery. Such an application has the potential to benefit cardiac oxygenation, tissue metabolic status and quicken recovery following the stoppage of the heart. PFCE's could also be used in supplying devascularized organs with oxygen prior to transplantation. Along those same lines, they could be used to perfuse the myocardium or brain tissue in heart attacks and strokes, oxygenating obstructed regions due to blockage and hopefully improving survival and recovery. Another possible area of application is in cancer therapy. PFCE's could increase the oxygenation of tumors, consequently benefiting radiation and/or chemotherapy in cancer treatment. Chemotherapeutic drugs could beadded 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 in the necrosis of cancer cells. This is especially promising in the treatment of cancers of the head and neck regions which are currently difficult to treat. Other possible applications include the treatment of fungal/bacterial skin and GI tract infections, oxygen deficient conditions (i.e. carbon monoxide poisoning), Alzheimer's Disease and medical imaging. The image to the right is a picture taken of a mouse completely submerged in liquid perfluorocarbon and still breathing!
Webpage designed in April 2005 by students of Brown University (Organ Replacement 108, Prof. Lysaght) Evan Werlin, Garland McQuinn, Gabriel Lepine, Ruth Ophardt

Contents

The Basics

Game On

The Major Players

To Infinity and Beyond…