Virus Photoinactivation in Stroma-free Hemoglobin with Methylene Blue or 1,9-dimethylmethylene Blue

Hirayama, Junichi; Wagner, Stephen J.; Gomez, Charlotte; Macdonald, Victor W.; Abe, Hideki; Ikeda, Hisami; Ikebuchi, Kenji; Sekiguchi, Sadayoshi

doi:10.1562/0031-8655(2000)071<0090:vpisfh>2.0.co;2

Cited by 6 publications

(2 citation statements)

References 16 publications

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“…12) Activation of DMMB monomer resulted in virus inactivation without MetHb formation. 11) Compared with the monomer, larger dimer may sterically prevent binding of the dyes to major or minor grooves of nucleic acids in virus particle. These collectively suggest that the monomer has high affinity to not only naked nucleic acid but also nucleic acid in virus particles.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of Reactive Oxygen Species in Hemoglobin Oxidation and Virus Inactivation by 1,9-Dimethylmethylene Blue Phototreatment.

Hirayama

Wagner

Abe

et al. 2001

Biological & Pharmaceutical Bulletin

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The viral safety of blood products has been significantly enhanced as a consequence of improvements in donor screening. However, there are still measurable risks of viral transmission through blood products.1,2) Therefore, processes for the removal and/or inactivation of viruses may represent an additional level of safety for these biological materials.Hemoglobin derived from human red blood cells is being used to develop a variety of artificial oxygen carriers. [3][4][5] Out-dated red cells for transfusion are an important source of human hemoglobin for the development of artificial oxygen carriers. The usual techniques for virus removal or inactivation, respectively, in stroma-free hemoglobin (SFH) are filtration and heat-treatment. [6][7][8] However, a combination of at least two techniques, which have different mechanisms of action, is important for complete elimination. This is the approach that has been adopted for the sterilization of a variety of pooled plasma derivatives and could have implications for a pooled hemoglobin product.Photosensitizers have been utillized for virus inactivation of blood products.9,10) We have previously reported on virus photoinactivation in SFH by 1,9-dimethylmethylene blue (DMMB).11) Vesicular stomatitis virus (VSV) was inactivatedϾ6 log 10 by DMMB without Met-Hb formation using 1 mM DMMB and red (655 nm) LED light.11) These conditions favor activation of monomer DMMB, which has an absorption peak of ca. 650 nm. In other experiments, the requirement of oxygen for virus photoinactivation by DMMB was demonstrated by the failure to achieve inactivation in samples bubbled with nitrogen.12)The absorption spectrum of DMMB in aqueous solutions has two peaks, which represent light absorption from the monomer and dimer forms.12) Activation of the dimer (max 590 nm), in contrast to monomer, resulted in virus photoinactivation with photooxidation of hemoglobin to methemoglobin (Met-Hb).11) It was speculated that compared with the dimer, the monomer of DMMB has high affinity to nucleic acids and so inactivates virus without inducing Met-Hb formation. However, why Met-Hb forms on exposure to activated dimer but not monomer may also be explained by a difference in the reactive oxygen species (ROS) involved in the four events (virus inactivation by monomer DMMB, virus inactivation by dimer DMMB, Met-Hb formation by monomer DMMB and Met-Hb formation by dimer DMMB). Methylene blue (MB) is known to produce not only singlet oxygen but also other ROS. 13,14) Therefore, DMMB, which is a derivative of MB, may also produce ROS other than singlet oxygen. In order to clarify which ROS are involved in virus inactivation and Met-Hb formation by activated monomer or dimer DMMB, the extent of the inactivation and formation in the presence or absence of ROS scavengers, quenchers or enhancer was evaluated. MATERIALS AND METHODSVirus Assays Bacteriophage R17 and its host, Escherichia coli Hfr C, were obtained from David Cook (Cerus Corporation, Concord, CA, U.S.A.). The plaque assay for bacteriophage R17 ...

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Section: Discussionmentioning

confidence: 99%

“…Since Met-Hb did not form under conditions in which VSV was inactivated by 6 log 10 , 11) experiments were conducted under harsher con- Met-Hb formation by activated monomer DMMB was suppressed (62%) by the addition of 1 mM rutin, which inhibited not only singlet oxygen but also other ROS (Fig. 3).…”

Section: Met-hb Formation On Dmmb Phototreatmentmentioning

confidence: 99%

Involvement of Reactive Oxygen Species in Hemoglobin Oxidation and Virus Inactivation by 1,9-Dimethylmethylene Blue Phototreatment.

Hirayama

Wagner

Abe

et al. 2001

Biological & Pharmaceutical Bulletin

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Protecting the Blood Supply From Emerging Pathogens: The Role of Pathogen Inactivation

Allain

Bianco

Blajchman

et al. 2005

Transfusion Medicine Reviews

113

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Although the risk of infection by blood transfusion is relatively low, breakthrough infections still occur, Transfusion-related fatalities caused by infections continue to be reported, and blood is not tested for many potentially dangerous pathogens. The current paradigm for increasing the safety of the blood supply is the development and implementation of laboratory screening methods and restrictive donor criteria. When considering the large number of known pathogens and the fact that pathogens continue to emerge, it is clear that the utility of new tests and donor restrictions will continue to be a challenge when considering the cost of developing and implementing new screening assays, the loss of potential donors, and the risk of testing errors. Despite improving the safety of blood components, testing remains a reactive approach to blood safety. The contaminating organisms must be identified before sensitive tests can be developed. In contrast, pathogen inactivation is a proactive strategy designed to inactivate a pathogen before it enters the blood supply. Almost all pathogen inactivation technologies target nucleic acids, allowing for the inactivation of a variety of nucleic acid-containing pathogens within plasma, platelets, or red blood cells thus providing the potential to reduce transfusion-transmitted diseases. However, widespread use of a pathogen inactivation technology can only be realized when proven safe and efficacious and not cost-prohibitive.

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Glutaraldehyde inactivation of enveloped DNA viruses in the preparation of haemoglobin-based oxygen carriers

Feng

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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Glutaraldehyde (GA), used medically as a disinfectant and as a crosslinker for haemoglobin (Hb)-based oxygen carriers (HBOCs), was investigated for its ability to inactivate viruses during the preparation of these artificial blood substitutes. Porcine parvovirus (PPV; a non-enveloped DNA virus) and porcine pseudorabies virus (PRV; an enveloped DNA virus) were used as the virus indicators. Upon treatment with 0.1 mM GA, the titer of PRV decreased from 9.62 log to 2.62 log within 0.5 h, whereas that of PPV decreased from 7.00 log to 2.30 log in 5 h. Following treatment with 1.0 mM GA, the titer of PRV decreased from 11.00 log to 1.97 log within 0.5 h, whereas that of PPV decreased from 7.50 log to 3.43 log in 4.5 h. During the polymerization of Hb with GA, the GA concentration decreased to 1.0 and 0.1 mM within 30 and 50 min, respectively, at a GA:Hb molar ratio of 10:1, whereas at a GA:Hb molar ratio of 30:1, GA decreased to those same concentrations in 1.5 and 2.5 h, respectively. This rapid decrease in GA concentration during its polymerization with Hb indicates that GA must be added into the Hb solution in a short time in order to get as high a initial concentration as possible. In this study, the GA can only inactivate PRV effectively, given that a longer time (4.5 h) was required for it to inactivate the PPV titer. This study therefore demonstrates that GA inactivates the enveloped DNA virus only during the preparation of HBOCs.

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Virus Photoinactivation in Stroma-free Hemoglobin with Methylene Blue or 1,9-dimethylmethylene Blue

Cited by 6 publications

References 16 publications

Involvement of Reactive Oxygen Species in Hemoglobin Oxidation and Virus Inactivation by 1,9-Dimethylmethylene Blue Phototreatment.

Involvement of Reactive Oxygen Species in Hemoglobin Oxidation and Virus Inactivation by 1,9-Dimethylmethylene Blue Phototreatment.

Protecting the Blood Supply From Emerging Pathogens: The Role of Pathogen Inactivation

Glutaraldehyde inactivation of enveloped DNA viruses in the preparation of haemoglobin-based oxygen carriers

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