Ultrapure, stroma-free, polymerized bovine hemoglobin solution: Evaluation of renal toxicity

Lee, R.; Atsumi, Naho; Jacobs, Edward E.; Austen, W. Gerald; Vlahakes, Gus J.

doi:10.1016/0022-4804(89)90092-9

Cited by 62 publications

(25 citation statements)

References 12 publications

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“…Six rats (c 200-250 g) were used for each exchange transfusion study. The animals were anesthetized and the femoral vein was cannulated with a polyethylene catheter connected by a three-way sterile stopcock to two syringes (Lee et al, 1989) one used for phlebotomy and the other for infusion of sample solution (DeVenuto et al, 1977). Exchange transfusion was performed by removal one mL of blood and immediate infusion of one mL of sample solution, repeating the process until the desired exchange level was achieved.…”

Section: Animal Studiesmentioning

confidence: 99%

“…To decrease its oxygen affinity, Hb has been modified by pyridoxylation and followed by polymerization with glutaraldehyde (DeVenuto and Zegna, 1983;Lee et al, 1989;Marini et al, 1990;Sehgal et al, 1983). Keipert and Chang (1985) demonstrated that intermolecular polymerization of PLP-Hb can yield a product with a longer vascular retention time and at the sample time with a lower oxygen affinity than the unmodified Hb.…”

Section: Introductionmentioning

confidence: 99%

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A natural compound (reuterin) produced by Lactobacillus reuteri for hemoglobin polymerization as a blood substitute

Chen

Chang

et al. 2004

Biotech & Bioengineering

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Stroma-free hemoglobin (Hb) has been modified by pyridoxylation and followed by polymerization with glutaraldehyde as a blood substitute. Nevertheless, the reaction rate of pyridoxylated Hb (PLP-Hb) with glutaraldehyde is too fast to control its molecular weight distribution. Additionally, it was reported that glutaraldehyde is cytotoxic even at low doses. To overcome these problems, another aldehyde, beta-hydroxypropionaldehyde (beta-HPA), was used in the study to polymerize hemoglobin (PLP-Hb). beta-HPA is a natural compound (reuterin) produced by Lactobacillus reuteri. It was found that the maximum degree of PLP-Hb polymerization by reuterin (RR-PLP-Hb) was approximately 40% if the formation of high molecular (> 500 kDa) polymers should be prevented. In contrast, at the same reaction condition, the glutaraldehyde-polymerized PLP-Hb solution became gel-like, due to overpolymerization. This indicated that the rate of PLP-Hb polymerization by reuterin was significantly slower than that by glutaraldehyde. With increasing the reaction temperature, PLP-Hb concentration, or reuterin-to-PLP-Hb molar ratio, the time to reach the maximum degree of PLP-Hb polymerization by reuterin became significantly shorter. Removal of unpolymerized PLP-Hb from the RR-PLP-Hb solution can be effectively achieved by a gel-filtration column. The P(50) value of the unmodified Hb solution was 14 torr, while that of the RR-PLP-Hb solution was 20 torr, an indication of lower oxygen affinity. Additionally, the oxygen-Hb dissociation curves for both test solutions had a sigmodial shape and a nearly 100% saturation at 100 torr. In the in vivo study, it was found that the animals treated with the RR-PLP-Hb solution all survived and remained healthy more than 3 months. In contrast, only one out of six rats survived for the control group treated with the unmodified Hb solution. Furthermore, it was found that the RR-PLP-Hb solution resulted in a significantly longer circulation time ( approximately 12 h) than the unmodified Hb solution ( approximately 1.5 h). These results suggest that the reuterin-polymerized PLP-Hb solution may be a new option in the development of blood substitutes.

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Section: Animal Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A natural compound (reuterin) produced by Lactobacillus reuteri for hemoglobin polymerization as a blood substitute

Chen

Chang

et al. 2004

Biotech & Bioengineering

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“…Tierexperimentelle Untersuchungen und erste Erfahrungen an Probanden haben gezeigt, daß ultragereinigtes polymerisiertes Rinderhämoglobin (HBOC-201) keine toxischen Nebenwirkungen auf Blutgerinnung, Leberund Nierenfunktion besitzt [17,20,30]. Bovines Hämoglobin wird nach Hämo-lyse der Erythrozyten durch Ultrafiltration, Separation und Chromatographie gereinigt, mit Glutaraldehyd zu Polymeren vernetzt und kann in desoxygenierter Form bei Raumtemperatur mehr als 2 Jahre gelagert werden.…”

Section: Präoperative Hämodilution Mit Bovinem Hämoglobinunclassified

Präoperative Hämodilution mit bovinem Hämoglobin

et al. 1997

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“…In the past, these remnants caused renal failures and coagulation disorder [50,51] but disappeared with the new purification techniques. While significant increase of serum creatinine was seen after administration of unpurified bovine hemoglobin in rats, a dose of 75 ml/kg of an ultrapurified preparation combined with bicarbonate did not cause changes in creatinine concentrations [52]. In a study with dogs, no acute hepatorenal disorders or pathological histological and ultrastructural changes in liver and kidneys were seen after nearly complete blood exchange with ultrapurified bovine hemoglobin [53].…”

Section: Hemoglobin Solutionsmentioning

confidence: 99%

Artificial Oxygen Carriers as Red Blood Cell Substitutes – Perfluorocarbons and Cell-Free Hemoglobin

Standl¹

2000

Transfus Med Hemother

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Forthcoming shortfall of blood products and persisting concerns about viral transmission and immunosuppressive side effects of allogeneic blood transfusion have reinforced the studies with alternative oxygen carriers in the last years. Modern perfluorochemicals and cell-free hemoglobin solutions can be applied without prior cross-matching and are now available as stable formulations with long shelf life. Both groups of oxygen carriers have shown their effectivity and tolerability in numerous animal studies. An emulsion of perflubron which has a 60% weight/volume relation is actually undergoing phase III studies with respect to its effectivity in augmented acute normovolemic hemodilution since it has been shown to reverse hemodynamic transfusion triggers. While clinical studies with human cross-linked hemoglobin (DCLHb) have been stopped last year because of the results of two clinical trials showing an increased mortality in patients with stroke and multiple injury shock being treated with DCLHb in comparison with saline, a phase III study with polymerized bovine hemoglobin HBOC-201 is actually being performed in noncardiac patients with perioperative bleeding. The objective of this multicenter study is to show that treatment with HBOC-201 can reduce or avoid allogeneic RBC transfusion. Besides its use in clinical transfusion protocols, artificial oxygen carriers have a unique potential to deliver oxygen to the tissues by plasmatic transport due to its different physiology of oxygenation when compared with conventional oxygenation provided by red blood cells. Future studies must show if these modern oxygen carriers are able to improve outcome of patients with impaired perfusion and organ oxygenation.

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Ultrapure, stroma-free, polymerized bovine hemoglobin solution: Evaluation of renal toxicity

Cited by 62 publications

References 12 publications

A natural compound (reuterin) produced by Lactobacillus reuteri for hemoglobin polymerization as a blood substitute

A natural compound (reuterin) produced by Lactobacillus reuteri for hemoglobin polymerization as a blood substitute

Präoperative Hämodilution mit bovinem Hämoglobin

Artificial Oxygen Carriers as Red Blood Cell Substitutes – Perfluorocarbons and Cell-Free Hemoglobin

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