ROBERT W WINSLOW

..Comparison of oxygen carriers with more traditional starch-based products provides new insight into the interaction of oxygen transport, microvascular perfusion, and blood volume expansion...

..After more than a century of research, one of these new solutions should find use as an alternative to red cells for transfusion in certain clinical settings...

..Preservation of functional capillary density and prevention of vasoconstriction further contribute to the effectiveness of this new formulation. MP4 is currently being tested in humans...

..We conclude that, despite its low PO2 necessary to obtain 50% O2, MP4 effectively substitutes for red blood cell hemoglobin in its ability to oxygenate tissues in extreme hemodilution...

..Such products may seem counterintuitive by traditional standards, but it is hoped that they will be less toxic, more beneficial to patients, and more economical to produce...

..It is possible that one or more of the earlier products may be approved by regulatory agencies in 1 or 2 years. However, a universally compatible and safe product most likely will be unavailable for several more years...

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..These include increased O2 affinity (low P50) and increased viscosity and oncotic pressure. These second-generation solutions hold greater promise for clinical development...

..Because of its low P50 and increased molecular size, the release of O2 in resistance vessels (arterioles) by Hemospan is restricted, and vasoconstriction is greatly reduced...

..Preservation of functional capillary density and prevention of vasoconstriction further contribute to the effectiveness of this new formulation...

..CONCLUSION: These data demonstrate that restoration of oxygen delivery with a small volume of MP4 yields significant recovery from hemorrhage without systemic vasoconstriction...

..Microvascular resistance in arterioles with a diameter range of 70-80 microm showed an increase relative to control with alpha alpha Hb, whereas MP4 caused a decrease...

..The model predicts that regardless of size, hemoglobin solutions with higher p50 will present excess O(2) to arteriolar walls. Oversupply of O(2) to arteriolar walls may cause constriction and paradoxically reduced capillary perfusion...

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..No significant elevation in mean arterial pressure was observed. CONCLUSION: MP4 appears to be free of a pressor effect, a major limitation to the development of a safe and effective RBC substitutes in the past...

..Higher O2 extraction of both red blood cell and plasma hemoglobin in capillaries represents a new mechanism of action of cell-free hemoglobin. High O2 affinity appears to be an important property for cell-free hemoglobin solutions...

..These results demonstrate that MP4 is safe and is without hemodynamic effects when administered as an exchange transfusion of 30% of estimated blood volume...

..This study evaluated resuscitation with MP4 after uncontrolled hemorrhage in anesthetized swine, and compared the effects of MP4 alone with those of standard-of-care crystalloid or crystalloid + blood...

..5 cP, colloid osmotic pressure of 49 mm Hg, and p50 of 5.5 mm Hg, improves systemic and microvascular variables after hemorrhage compared with shed blood (SB) and 5% hydroxyethyl starch (HES)...

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..MP4 was compared with hydroxyethyl starch solutions of differing concentrations (ie, HES 260/0.45 and HES 130/0.4)...

..Phase III trials in orthopedic surgery have recently completed enrollment in Europe...

..7 cP (vs. 2.5 cP for MalPEG-Hb). The present results show that both solutions are efficacious plasma expanders and that the hemoglobin-based solution provides improved oxygen distribution and tissue Po2 in the hamster chamber model...

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..Alternatively, the unique O2-binding characteristics with low p50 and co-operativity suggest that the 'R-state' conformation of MalPEG-Hb is in a more T-state configuration and restricted from conformational change...

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..A phase I clinical trial of MP4 was undertaken to evaluate whether MP4 elicits the clinical side effects associated with previous hemoglobin-based solutions...

..MP4 was significantly higher than MPA (P < 0.05) and was not statistically different from baseline, an effect due to the additional oxygen release to the tissue by the Hb MP4...

..The proposed methodology for assessment of low-resolution structures and interactions is a powerful means for rational design of PEGylated therapeutic agents...

..The results demonstrate that a non-hypertensive PEG-Hb can be generated by conjugation of a lower number of PEG chains than previously reported...

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..The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken...

..The research described in this proposal will focus on molecules and formulations specifically tailored for use in prehospital and trauma settings. ..