Preclinical safety assessment of pathogen reduced red blood cells treated with amustaline and glutathione
| العنوان: | Preclinical safety assessment of pathogen reduced red blood cells treated with amustaline and glutathione |
|---|---|
| المؤلفون: | Theresa Sullivan, Laurence Corash, Nina Mufti, Anne North |
| المصدر: | Transfusion |
| بيانات النشر: | John Wiley & Sons, Inc., 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Erythrocytes, Immunology, 030204 cardiovascular system & hematology, Pharmacology, medicine.disease_cause, Chromosome aberration, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, In vivo, medicine, Blood-Borne Pathogens, Immunology and Allergy, Blood Components, Animals, Humans, Lymphocytes, Carcinogen, Micronucleus Tests, Chemistry, Hematology, Glutathione, In vitro, Amustaline, Micronucleus test, Nitrogen Mustard Compounds, Acridines, Virus Inactivation, Female, Tumor Suppressor Protein p53, Erythrocyte Transfusion, Genotoxicity, 030215 immunology |
| الوصف: | BACKGROUND The nucleic acid targeted pathogen reduction (PR) system utilizing amustaline (S‐303) and glutathione (GSH) is designed to inactivate blood‐borne pathogens and leukocytes in red blood cell concentrates (PR‐RBCC). Inactivation is attained after amustaline intercalates and forms covalent nucleic acid adducts preventing replication, transcription, and translation. After pathogen inactivation, amustaline spontaneously hydrolyzes to S‐300, the primary negatively charged reaction product; amustaline is below quantifiable levels in PR‐RBCC. GSH quenches free unreacted amustaline. STUDY DESIGN AND METHODS The genotoxic and carcinogenic potential of PR‐RBCC, the reaction by‐products, and S‐300 were assessed in accordance with the International Conference on Harmonization (ICH) guidelines and performed in compliance with the Food and Drug Administration (FDA) good laboratory practice standards, 21 CFR Part 58. in vitro bacterial reverse mutagenicity and chromosomal aberration assays were performed with and without exogenous S9 metabolic activation, and in in vivo clastogenicity and carcinogenic assays using validated murine models. RESULTS PR‐RBCCs were not genotoxic in vitro and in vivo and were non‐carcinogenic in p53+/− transgenic mice transfused over 26 weeks. Estimated safety margins for human exposure ranged from >90 to >36 fold for 2 to 5 PR‐RBCCs per day, respectively. PR‐RBCCs and S‐300 did not induce chromosome aberration in the in vivo murine bone marrow micronucleus assay at systemically toxic doses. CONCLUSIONS PR‐RBCCs did not demonstrate genotoxicity in vitro or in vivo and were not carcinogenic in vivo. These studies support the safety of PR‐RBCCs and suggest that there is no measurable genotoxic hazard associated with transfusion of PR‐RBCCs. |
| اللغة: | English |
| تدمد: | 1537-2995 0041-1132 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36dcb2dec72b763023c14705d7c10c4c http://europepmc.org/articles/PMC7027779 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....36dcb2dec72b763023c14705d7c10c4c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15372995 00411132 |
|---|