OxyVita

Oxyvita Hb is a novel zero-linked polymerized hemoglobin based oxygen carrier (HBOC) developed by a research group at the University of Maryland, Baltimore under the direction of Dr. Enrico Bucci. This polymeric HBOC is being developed as an alternative to blood transfusion for the delivery of oxygen for a range of clinical situations. It will reduce the need for human blood donors and lower the risks associated with blood transfusion. Presently, this HBOC is being developed and manufactured by OXYVITA, Inc, New Windsor, New York. It is undergoing pre-clinical studies in collaboration with several medical institutions throughout the United States.

Clinical Issues

During the past two decades a number of significant problems associated with the development and testing of other acellular HBOCs have been associated with several different acellular HBOC molecules functioning outside of the red blood cell environment. These problems include observations of:

* Elevated incidences of renal failure.
* Increased blood pressure due to vasoconstriction related to the sequestering of NO by the hemoglobin molecules that have extravasated through vessel walls into the lymphatic tissue.
* Toxic responses resulting from chemical residues associated with the polymerization processes.
* Redox instability leading to rapid oxidation (methemoglobin formation) of many these earlier HBOCs.

Molecular Properties

Unique physiochemical characteristics of Oxyvita Hb have been designed into this HBOC to specifically address each of these concerns. Through a novel synthetic process, polymerization is achieved by activating the carboxyl groups located on the hemoglobin surface to react with lysyl residues on the surface of adjacent molecules wherein no chemical residue remains within the polymer. This process leads to a “zero-linked” polymerized hemoglobin resulting in the formation of a very large super-polymer that does not extravasate from the circulatory system, reducing dramatically the most serious side effects of previously developed HBOCs. Taking advantage of the zero-linked polymerization process, it is possible to apply this method to a wide variety of mammalian hemoglobins.

The usual polymerized product has an average hydrodynamic radius of 210A exhibiting a low osmotic pressure (<10% of tetrameric Hb) and a viscosity at 6 g/dl similar to human plasma. Due to its large molecular size, an intravascular time greater than 10 hours (in cats) has been observed. Unlike many other tested HBOCs, OxyVita Hb possesses a rather low P50 and exhibits low cooperativity (n=1.2).STORAGE Properties

Productions

* Solution form
* Powder form

Benefits

The major physical characteristic of OxyVita Hb is its macromolecular size (average Molecular Weight = 17MDa), providing a distinct advantage by reducing vascular extravasation. Reducing extravasation leaves endogenous NO to control muscular relaxation within the venous and arterial walls helping to maintain normal blood pressure (MAP) and lower the possibility of renal failure. The previous use of lower molecular weight polymerized non-dissociating HBOCs did initially bring about a reduction in the elimination of these HBOCs through the glomerular capillaries, but an increase in MAP was still observed due to their extravasation into the lungs and peritoneum. An immediate signal of hemoglobin toxicity is the observation of an increase in MAP in the infused animals. No increase in MAP has been observed for OxyVita Hb within several pre-clinical studies using cats and various other mammals.

A key question for OxyVita Hb is simply, “does this HBOC deliver oxygen in vivo?” Initial evidence confirming a positive response to this question was shown in a study which involves a 50% isovolemic exchange transfusion of OxyVita in cats. This exchange within the cat produced vasoconstriction of the pial arterioles in the brain with no MAP increase. In contrast, an equivalent hemodilution with albumin produced vasodilation and an increased blood flow. Given that the only difference between the two transfusions was the oxygen carried by OxyVita Hb, the absence of a MAP increase following a vasoconstriction indicates that vasoconstriction was a regulatory process preventing excessive oxygen delivery to the brain by OxyVita Hb when the blood viscosity was reduced by the exchange transfusion.

To further confirm physiological improvements with the use of OxyVita Hb, a 50% exchange transfusion using OxyVita Hb was shown to reduce the infarct size induced with mice brains. A reduction in infraction volume from 110 mm3 to 58 mm3 was observed for a middle cerebral artery occlusion. [Bucci, E., Rasynaska, A., Kwansa, H., Matheson-Urbaitis, B., O’Hearne, M., Ulatowski, J.A. and Koehler, R.C. (1996) J. Lab Clin Med 128, 146-153.] [Estep, T., Bucci, E., Farmer, M., Greenburg, G., Harrington, J.P., Kim, H.W., Klein, H., Mitchell, P., Nemo, G., Olsen, K., Palmer, A., Valeri, C.R. and Winslow, R.M. (2008) Transfusion January 7 (Epub).] [Hirsch, R.E. and Harrington, J.P. (2000) Einstein Quart. J. Biol. Med. 27, 123-134.] [Jahr, J.S., Walker, V. and Manoochehri, K. (2007) Curr. Opin. Anaesthesiol. 20, 325-330.Matheson, B., Kwansa, H., Bucci, E., Rebel, A. and Koehler, R.C. (2002) J. Appl. Physiol. 93, ] [Ness, P.N. and Cushing, M.M. (2007) Arch Pathol Lab Med 131, 734-741.] [Rohlfs, R.J., Bruner, E., Chiu, A., Gonzales, A., Gonzales, M.L., Magde, D., Magde, M.D., Vandergriff, K.D. and Winslow, R.M. (1998) J. Biol. Chem. 273, 12128-12134.] [Winslow, R.M. (2007) Semin. Hematol. 44, 51-59.]

References/External Links