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Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
PURPOSE: Undesirable complement (C) activation by nanomedicines can entail an adverse immune reaction known as C activation-related pseudoallergy (CARPA) in sensitive patients. The syndrome includes cardiopulmonary, hemodynamic, and a variety of other physiological changes that have been well descri...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396670/ https://www.ncbi.nlm.nih.gov/pubmed/30880965 http://dx.doi.org/10.2147/IJN.S187139 |
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author | Őrfi, Erik Mészáros, Tamás Hennies, Mark Fülöp, Tamás Dézsi, László Nardocci, Alexander Rosivall, László Hamar, Péter Neun, Barry W Dobrovolskaia, Marina A Szebeni, János Szénási, Gábor |
author_facet | Őrfi, Erik Mészáros, Tamás Hennies, Mark Fülöp, Tamás Dézsi, László Nardocci, Alexander Rosivall, László Hamar, Péter Neun, Barry W Dobrovolskaia, Marina A Szebeni, János Szénási, Gábor |
author_sort | Őrfi, Erik |
collection | PubMed |
description | PURPOSE: Undesirable complement (C) activation by nanomedicines can entail an adverse immune reaction known as C activation-related pseudoallergy (CARPA) in sensitive patients. The syndrome includes cardiopulmonary, hemodynamic, and a variety of other physiological changes that have been well described in man, pigs, dogs, and rats. However, the information on CARPA is scarce and ambiguous in mice, a species widely used in preclinical studies. The present study aimed to fill this gap by exploring signs of CARPA in mice following i.v. administration of AmBisome and Abelcet, which are nano-formulations of Amphotericin B with high risk to cause CARPA. MATERIALS AND METHODS: Anesthetized NMRI mice were intravenously injected with liposomal amphotericin B (Abelcet and AmBisome; 30–300 mg phospholipid/kg), drug-free high cholesterol multilamellar vesicles (HC-MLV), and positive controls, cobra venom factor (CVF) and zymosan, followed by the measurement of blood pressure (BP), heart rate, white blood cell, and platelet counts and plasma thromboxane B2 (TXB2) levels. C activation was assessed by C3a ELISA, a C3 consumption assay (PAN-C3) and a modified sheep red blood cell hemolytic assay. RESULTS: All test agents, except HC-MLV, caused transient hypertension, thrombocytopenia, and elevation of plasma TXB2, which were paralleled by significant rises of plasma C3a in CVF and zymosan-treated animals, wherein the initial hypertension turned into hypotension and shock. Abelcet and AmBisome caused minor, delayed rise of C3a that was not associated with hypertension. The C3a receptor inhibitor SB-290157 attenuated the hypertension caused by Abelcet and decreased the BP thereafter. CONCLUSION: The parallelism between C3a anaphylatoxin production and severity of physiological changes caused by the different agents is consistent with CARPA underlying these changes. Although the reactive dose of liposomal phospholipids was substantially higher than that in other species (pigs, dogs), the mouse seems suitable for studying the mechanism of hypersensitivity reactions to liposomal formulations of amphotericin B, a frequent side effect of these drugs. |
format | Online Article Text |
id | pubmed-6396670 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63966702019-03-15 Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice Őrfi, Erik Mészáros, Tamás Hennies, Mark Fülöp, Tamás Dézsi, László Nardocci, Alexander Rosivall, László Hamar, Péter Neun, Barry W Dobrovolskaia, Marina A Szebeni, János Szénási, Gábor Int J Nanomedicine Original Research PURPOSE: Undesirable complement (C) activation by nanomedicines can entail an adverse immune reaction known as C activation-related pseudoallergy (CARPA) in sensitive patients. The syndrome includes cardiopulmonary, hemodynamic, and a variety of other physiological changes that have been well described in man, pigs, dogs, and rats. However, the information on CARPA is scarce and ambiguous in mice, a species widely used in preclinical studies. The present study aimed to fill this gap by exploring signs of CARPA in mice following i.v. administration of AmBisome and Abelcet, which are nano-formulations of Amphotericin B with high risk to cause CARPA. MATERIALS AND METHODS: Anesthetized NMRI mice were intravenously injected with liposomal amphotericin B (Abelcet and AmBisome; 30–300 mg phospholipid/kg), drug-free high cholesterol multilamellar vesicles (HC-MLV), and positive controls, cobra venom factor (CVF) and zymosan, followed by the measurement of blood pressure (BP), heart rate, white blood cell, and platelet counts and plasma thromboxane B2 (TXB2) levels. C activation was assessed by C3a ELISA, a C3 consumption assay (PAN-C3) and a modified sheep red blood cell hemolytic assay. RESULTS: All test agents, except HC-MLV, caused transient hypertension, thrombocytopenia, and elevation of plasma TXB2, which were paralleled by significant rises of plasma C3a in CVF and zymosan-treated animals, wherein the initial hypertension turned into hypotension and shock. Abelcet and AmBisome caused minor, delayed rise of C3a that was not associated with hypertension. The C3a receptor inhibitor SB-290157 attenuated the hypertension caused by Abelcet and decreased the BP thereafter. CONCLUSION: The parallelism between C3a anaphylatoxin production and severity of physiological changes caused by the different agents is consistent with CARPA underlying these changes. Although the reactive dose of liposomal phospholipids was substantially higher than that in other species (pigs, dogs), the mouse seems suitable for studying the mechanism of hypersensitivity reactions to liposomal formulations of amphotericin B, a frequent side effect of these drugs. Dove Medical Press 2019-02-26 /pmc/articles/PMC6396670/ /pubmed/30880965 http://dx.doi.org/10.2147/IJN.S187139 Text en © 2019 Őrfi et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Őrfi, Erik Mészáros, Tamás Hennies, Mark Fülöp, Tamás Dézsi, László Nardocci, Alexander Rosivall, László Hamar, Péter Neun, Barry W Dobrovolskaia, Marina A Szebeni, János Szénási, Gábor Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title | Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title_full | Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title_fullStr | Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title_full_unstemmed | Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title_short | Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice |
title_sort | acute physiological changes caused by complement activators and amphotericin b-containing liposomes in mice |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396670/ https://www.ncbi.nlm.nih.gov/pubmed/30880965 http://dx.doi.org/10.2147/IJN.S187139 |
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