Blood Substitutes  

       Advantages of blood substitutes: 

Universal Compatibililty	Can be transfused to a person of any blood  type without any tests, saving   crucial emergency time.
Purity and Nontoxicity	Is composed of ultrapure compounds that  are free of infectious agents and   allergens, resulting in a non-toxic and disease-free product.
Storability	Does not deteriorate with storage and does  not need refrigeration, making   it ideal for disaster situations and remote areas.
Availabililty	Is composed of readily and reliably  available materials, insuring adequate   supplies for large-scale, economical manufacturing.
Predictability	Has ingredients that are all understood,   making it predictable and   manipulable

The two major approaches for artificial red blood cells are:

1. Modified hemoglobin. 2. Perfluorochemicals.   1. MODIFIED HEMOGLOBIN Hemoglobin can be extracted from red cells by removing the cell membranes to form stroma-free hemoglobin. However, this cannot be used as blood substitutes for your renal toxicity and insufficient  release of oxygen. To prevent these problems, two biotechnologies are developed: 1. Encapsulated hemoglobin 2. Crosslinked hemoglobin (polyemoglobin, intramolecularly crosslinked hemoglobin and cojugated hemoglobin). Hemoglobin can have also obtained by means of the recombinant technology: recombinant hemoglobin.

 CLINICAL TRIAL UPDATE

Company	Product	Phase
BAXTER	recombinant human hemoglobin - Baxter is working on a "next generation" hemoglobin-based oxygen carrying solution, which is produced using recombinant technology (vs. others that may be derived from human or animal red blood cells). To produce the recombinant hemoglobin therapeutic, the human gene responsible for producing hemoglobin is copied. For Baxter's new recombinant hemoglobin solution, this gene has been modified with the intent to enhance the stability and functionality of the hemoglobin therapeutic. This modification has the potential to reduce the side effects of the therapy. Copies of the gene are then inserted into the DNA of a highly controlled population of E. coli bacteria, where information encoded on the genes instructs the bacteria to produce hemoglobin. The recombinant hemoglobin solution is then collected and undergoes rigorous purification steps during its processing.	phase one clinical trials in the USA
BIOPURE	crosslinked bovine polyhemoglobin - first generation blood substitute: Hemopure consists of chemically stabilized bovine hemoglobin formulated in a balanced salt solution. On a gram-for-gram basis, this cross-linked hemoglobin carries the same amount of oxygen as the hemoglobin in red blood cells. However, these linked hemoglobin molecules circulate in plasma, and are smaller, have lower viscosity (resistance to flow) and more readily release oxygen to tissues than red blood cells. Consequently, they can carry oxygen at low blood pressure and can carry oxygen through constricted or partially blocked blood vessels to areas of the body that red blood cells cannot reach due to their larger size (VIDEO 1Normal; 2Anemic; 3Hemopure).	approved in South Africa for the treatment of adult surgical patients who are acutely anemic In October 2002, the U.S. Food and Drug Administration (FDA) accepted for review Biopure's biologic license application (BLA) to market Hemopure in the United States for a similar indication in orthopedic surgical patients. This acceptance is the first time a hemoglobin-based oxygen therapeutic for human use has reached this stage in the U.S. regulatory process. On July 30, 2003, the FDA issued Biopure a letter requesting additional information and suspending the BLA review clock. The company is now preparing a comprehensive written response to these questions.
HEMOSOL	crosslinked human polyhemoglobin - first generation blood substitute	phase three clinical trials
NORTHFIELD	crosslinked human polyhemoglobin - first generation blood substitute: PolyHeme® is a solution of chemically modified hemoglobin derived from human blood. Hemoglobin is the oxygen-carrying component of the human red blood cell. Northfield purchases donated blood from The American Red Cross and Blood Centers of America for use as the starting material for PolyHeme. The company uses a proprietary process of separation, filtration and chemical modification to produce PolyHeme. Hemoglobin is first extracted from red blood cells and filtered to remove impurities. The purified hemoglobin is next chemically modified using a multi-step process to create a polymerized form of hemoglobin designed to avoid the undesirable effects historically associated with hemoglobin-based blood substitutes, including vasoconstriction, kidney dysfunction, liver dysfunction and gastrointestinal distress. The modified hemoglobin is then incorporated into a solution which can be administered as an alternative to transfused blood. One unit of PolyHeme contains 50 grams of modified hemoglobin, approximately the same amount of hemoglobin delivered by one unit of transfused blood.	phase three clinical trial
SANGART	polyethylene glycol-modified human hemoglobin (MalPEG-Hb) - second generation blood substitute: HemospanTM combines low hemoglobin concentration with high oxygen transport capability. Hemoglobin is harvested from outdated human blood and combined with PEG to eliminate the toxicity of free hemoglobin. It has been shown in laboratory testing that pegylation of the hemoglobin is an effective shield against immunologic reactions. PEG-modified hemoglobins have the longest known circulating half-times (a half-time is the time at which one-half of the administered dose is still present in the circulation). In general, intramolecular-crosslinks lead to 12 hour half-time, polymerizations lead to 20 hour half-times.	phase Ib/II clinical trial in Sweden
SYNZYME	polymerized polynitroxyl hemoglobin - second generation blood substitute: HemoZyme, compared to current HBOCs, is: (a) a vasodilator, (b) an antioxidant enzyme mimetic, and (c) an anti-inflammatory agent. Consequently, HemoZyme can effectively prevent or treat ischemia, reperfusion, and inflammatory injuries and the post-reperfusion multiple organ failure that often follows severe ischemia/hemorrhage and resuscitation.	?

 

2. PERFLUOROCHEMICALS   Perfluorocarbons are being tested because they can carry  oxygen and carbon dioxide, the two gases handled by hemoglobin. Perfluorocarbons dissolve more oxygen  than any other inert liquid known. Now that phospholipid-stabilized emulsions can be made that show no complement activation, better results can be obtained. Both lower inspired oxygen levels and higher concentrations of perfluorochemicals are now possible, and rapid further developments in this area of blood substitutes should be possible.

 CLINICAL TRIAL UPDATE

Company	Product	Phase
ALLIANCE	Perfluoroctyl bromide with egg yolk lecitin (Oxygent)	phase three clinical trial
SANGUINE	Second-generation of the PFC emulsion, Fluosol (PHER-O2)	preclinical
S.B.I.	Oxycyte	preclinical
PERFTORAN	Perfluorodecalin+Perfluoromethylcyclohexylpiperidin (Perftoran)	permitted for the medical application in Russian Federation since 1997

 

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