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Dextran-Hemoglobin
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Dextran-Hemoglobin
Dextran-Hemoglobin is another hemoglobin based oxygen carrier. Dextran hemoglobin is prepared by conjugating human hemoglobin to dextran, a branched polysaccharide made of many glucose molecules joined into chains. The process utilizes coupling hemoglobin to bromo-Dextran, resulting in a very high yield. Dextran conjugation has many advantages:
- Dextran is readily available in a variety of molecular weights, and its production is fairly standardized
- It has been used as a clinical plasma volume expander, so its biocompatibility and safety have already been established
- Dextran is completely metabolized and excreted from the body after a brief storage period in cells
- It can be chemically modified by a variety of methods to form defined and stable compounds
Dextran has been used in drug delivery systems, and to prolong the plasma half lives of several compounds. Therefore it has been established already that dextran can increase the therapeutic efficacy of various proteins.
Advantages of Conjugation:
- Has been shown to prevent excretion of hemoglobin and kidney damage
- Slows down non-renal clearance of hemoglobin and Hemoglobin escape into extravascular space – this minimizes tissue edema and damage caused by iron overload.
- Decreased cost of treatment due to lower hemoglobin clearance
- Dextran-Hemoglobin binds and releases oxygen with an affinity that is 2.5 times that of normal hemoglobin
- Coupling decreases auto-oxidation of hemoglobin, increasing its effectiveness as an HBOC
- Coupling increases stability in the body including against acid denaturation and ethanol precipitation this has two important applications:
- Suggests conjugate solutions could be sterilized with organic solvents
- Provides an additional safeguard against precipitation and denaturation of hemoglobin in the bloodstream, which could lead to circulatory obstruction
In animal models dextran-hemoglobin has been the first soluble blood substitute to sustain complete recovery of animals that have had almost complete replacement of erythrocytes. Dextran-hemoglobin’s good performance as an HBOC is a result of:
- Long residence time in plasma, with a half life of up to 57 hours, compared to 22 hours for the first-generation of HBOCs
- Non-clearance through renal route, which protects the kidney function and structure
- Slow extravasation which limits tissue edema
- Long residence time leads to lower frequency of HBOC infusions required to maintain adequate hemoglobin. Paired with low concentration of 6% hemoglobin leads to greater treatment economy and lower imposed metabolic iron load
Although Dextran-Hemoglobin has so far mostly been tested in animal models, results have been very promising, and a clinical trial in humans is expected to begin by the end of this year in Thailand. A trial on dogs in Thailand is currently underway, and once that trial is finished the human trial will begin. The company hopes that regulatory approval will be cheaper and easier to acquire in Thailand, and that this approval, if granted, will aid the transition into the US and European markets.
While this technology seems to be an improvement over first generation HBOCs, it still has some limitations. Because it relies on human hemoglobin, an adequate blood supply is still needed. However, the product still has certain key advantages
- Blood has a maximum shelf-life of only 42 days and Dextran-Hemoglobin can be made from an older blood supply that can no longer be used for transfusion
- In the long run, it is anticipated that hemoglobin supplies will be met through the scientific production.
