Oxygen delivery during extreme anemia with ultra-pure earthworm hemoglobin

Elmer, Jacob; Palmer, Andre F.; Cabrales, Pedro

doi:10.1016/j.lfs.2012.08.036

Cited by 20 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Polymerization further increases half-life (Tam et al 1978, DeVenuto and Zegna 1983, Keipert and Chang 1983, Sehgal et al 1984, Keipert and Chang 1987, Snyder et al 1987, Berbers et al 1991, Lenz et al 1991, Hsia et al 1993, Bakker et al 1993, Anderson et al 1993, Lee et al 1995, Pearce et al 2003, Wicks et al 2003, Bonegio et al 2006, Buehler et al 2010, Baek et al 2012, Elmer et al 2012. Most reported values have not been corrected for blood volume changes, but the increased half-life of crosslinked and/or polymerized HBOCs relative to unmodifi ed Hb is not an artifact of such changes because these modifi cations do not increase the oncotic pressure at a given Hb concentration (DeVenuto 1983, Sehgal et al 1984, Berbers et al 1991).…”

Section: Plasma Half-life -Summary Data and Trendsmentioning

confidence: 99%

“…As noted in " Considerations and limitations " , the concentration of functional HBOC is reduced by oxidation to the inactive metHb form during storage and circulation (Kramlova et al 1976, DeVenuto 1978, Tam et al 1978, Sehgal et al 1981, Snyder et al 1987, Bush et al 1994, Lee et al 1995, Caron et al 2000, O ' Hara et al 2001, Sprung et al 2002, Wicks et al 2003, Olofsson et al 2006, Vandegriff et al 2006, Buehler et al 2010, Baek et al 2012, Elmer et al 2012. While the predominant oxidant during storage is oxygen, other oxidants are important intravenously, including hydrogen peroxide and nitric oxide (NO) (Brooks 1932).…”

Section: Functional Half-lifementioning

confidence: 99%

“…A 40 -80% reduction of high levels of oxidized HBOC was also observed by other authors in rats or guinea pigs, reinforcing the notion that mammalian blood exhibits substantial reducing potential (Snyder et al 1987;den Boer et al 1992. It should be noted that while the percentage of plasma metHb usually increases with time after HBOC infusion, the absolute concentration may increase, decrease, or stay relatively constant until the inevitable ultimate decrease (Tam et al 1978, Snyder et al 1987, Bush et al 1994, Lee et al 1995, O ' Hara et al 2001, Sprung et al 2002, Wicks et al 2003, Dunne et al 2006, Olofsson et al 2006, Vandegriff et al 2006, Buehler et al 2010, Baek et al 2012, Elmer et al 2012, depending on dose, recipient species, and HBOC type. One question which arises is whether HBOC oxidation facilitates plasma removal.…”

Section: Functional Half-lifementioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Estep¹

2015

Artificial Cells, Nanomedicine, and Biotechnology

View full text Add to dashboard Cite

The circulatory persistence, distribution, and metabolism of hemoglobin-based oxygen carriers (HBOCs) is a major determinant of their safety and efficacy. In this communication, published data on the pharmacokinetics and routes of plasma elimination of HBOCs are summarized and evaluated. The circulating half-life of HBOCs is dose-dependent in both animals and humans. Half-life also increases with molecular weight in animals, at least up to the MDa range. The functional half-life of HBOCs is diminished by as much as 40% due to oxidation of the heme group relative to the overall rate of removal of hemoglobin (Hb) from plasma. Kidney excretion of HBOCs is greatly diminished compared to that of unmodified Hb, but the liver remains a primary site of catabolism. Both hepatocytes and Kupffer cells have been implicated in receptor-mediated HBOC uptake. Removal also occurs in the spleen and/or bone marrow and probably at dispersed sites in the endothelium as well. HBOCs extravasate into the lymph at a rate inversely proportional to their molecular weight and are taken up by monocyte/macrophage CD163 receptors, both as free Hb and in complexes with haptoglobin (Hp). The interactions with both Hp and the CD163 receptor are altered by Hb modification. However, monocyte/macrophage uptake may not be a quantitatively important route for the removal of clinically relevant doses of HBOCs. The relative contributions of different removal pathways have yet to be comprehensively determined, particularly in humans.

show abstract

Section: Plasma Half-life -Summary Data and Trendsmentioning

confidence: 99%

Section: Functional Half-lifementioning

confidence: 99%

Section: Functional Half-lifementioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Estep¹

2015

Artificial Cells, Nanomedicine, and Biotechnology

View full text Add to dashboard Cite

show abstract

“…LtEc has been studied before as an O 2 carrier because it has a lower rate of oxidation [redox potential, Eo = 112 mV] compared to mammalian Hbs [Eo = -50 mV for HbA] [13]. Additionally, LtEc and other erythrocruorins have an extremely low rate of NO scavenging [14]. LtEc is a complex structure, containing 144 globin subunits and 36 linker proteins.…”

Section: Introductionmentioning

confidence: 99%

“…LtEc is a complex structure, containing 144 globin subunits and 36 linker proteins. The complex consists of five types of globins [A, B, C, and D1 or D2] and four types of linkers [14]. Each globin contains a heme group and binds O 2 .…”

Section: Introductionmentioning

confidence: 99%

Polyethylene Glycol Camouflaged Earthworm Hemoglobin

et al. 2017

Self Cite

View full text Add to dashboard Cite

Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals’ systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc’s already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic.

show abstract

Direct comparison of oligochaete erythrocruorins as potential blood substitutes

Zimmerman

DiIusto

Dienes

et al. 2017

Bioengineering & Transla Med

View full text Add to dashboard Cite

While many blood substitutes are based on mammalian hemoglobins (e.g., human hemoglobin, HbA), the naturally extracellular hemoglobins of invertebrates (a.k.a. erythrocruorins, Ecs) are intriguing alternative oxygen carriers. Specifically, the erythrocruorin of Lumbricus terrestris has been shown to effectively deliver oxygen in mice and rats without the negative side effects observed with HbA. In this study, the properties of six oligochaete Ecs (Lumbricus terrestris, Eisenia hortensis, Eisenia fetida, Eisenia veneta, Eudrilus eugeniae, and Amynthas gracilis) were compared in vitro to identify the most promising blood substitute candidate(s). Several metrics were used to compare the Ecs, including their oxidation rates, dissociation at physiological pH, thermal stability, and oxygen transport characteristics. Overall, the Ecs of Lumbricus terrestris (LtEc) and Eisenia fetida (EfEc) were identified as promising candidates, since they demonstrated high thermal and oligomeric stability, while also exhibiting relatively low oxidation rates. Interestingly, the O2 affinity of LtEc (P 50 = 26.25 mmHg at 37 °C) was also observed to be uniquely lower than EfEc and all of the other Ecs (P 50 = 9.29–13.62 mmHg). Subsequent alignment of the primary sequences of LtEc and EfEc revealed several significant amino acid substitutions within the D subunit interfaces that may be responsible for this significant change in O2 affinity. Nonetheless, these results show that LtEc and EfEc are promising potential blood substitutes that are resistant to oxidation and denaturation, but additional experiments will need to be conducted to determine their safety, efficacy, and the effects of their disparate oxygen affinities in vivo.

show abstract

Oxygen delivery during extreme anemia with ultra-pure earthworm hemoglobin

Cited by 20 publications

References 34 publications

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Polyethylene Glycol Camouflaged Earthworm Hemoglobin

Direct comparison of oligochaete erythrocruorins as potential blood substitutes

Contact Info

Product

Resources

About