Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice

Erik Őrfi,1,2 Tamás Mészáros,1,2 Mark Hennies,3 Tamás Fülöp,1,2 László Dézsi,1,2 Alexander Nardocci,1 László Rosivall,1,2 Péter Hamar,4,5 Barry W Neun,6 Marina A Dobrovolsk...

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Autores principales:	Őrfi E, Mészáros T, Hennies M, Fülöp T, Dézsi L, Nardocci A, Rosivall L, Hamar P, Neun BW, Dobrovolskaia MA, Szebeni J, Szénási G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Hypersensitivity infusion reactions zymosan cobra venom factor TXB2 cholesterol anaphylatoxins platelets Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/1310ff27dbfc4d2fb7b789a504b6712c
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id	oai:doaj.org-article:1310ff27dbfc4d2fb7b789a504b6712c
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Hypersensitivity infusion reactions zymosan cobra venom factor TXB2 cholesterol anaphylatoxins platelets Medicine (General) R5-920
spellingShingle	Hypersensitivity infusion reactions zymosan cobra venom factor TXB2 cholesterol anaphylatoxins platelets Medicine (General) R5-920 Őrfi E Mészáros T Hennies M Fülöp T Dézsi L Nardocci A Rosivall L Hamar P Neun BW Dobrovolskaia MA Szebeni J Szénási G Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
description	Erik Őrfi,1,2 Tamás Mészáros,1,2 Mark Hennies,3 Tamás Fülöp,1,2 László Dézsi,1,2 Alexander Nardocci,1 László Rosivall,1,2 Péter Hamar,4,5 Barry W Neun,6 Marina A Dobrovolskaia,6 János Szebeni,1,2,7,* Gábor Szénási1,8,* 1Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; 2SeroScience LCC., Cambridge, MA, USA; 3TECOdevelopment GmbH, Rheinbach, Germany; 4Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary; 5Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; 6Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA; 7Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary; 8Institute of Pathophysiology, Semmelweis University, Budapest, Hungary *These authors contributed equally to this work 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. Keywords: hypersensitivity, infusion reactions, zymosan, cobra venom factor, TXB2, cholesterol, anaphylatoxins, platelets
format	article
author	Őrfi E Mészáros T Hennies M Fülöp T Dézsi L Nardocci A Rosivall L Hamar P Neun BW Dobrovolskaia MA Szebeni J Szénási G
author_facet	Őrfi E Mészáros T Hennies M Fülöp T Dézsi L Nardocci A Rosivall L Hamar P Neun BW Dobrovolskaia MA Szebeni J Szénási G
author_sort	Őrfi E
title	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_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_sort	acute physiological changes caused by complement activators and amphotericin b-containing liposomes in mice
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/1310ff27dbfc4d2fb7b789a504b6712c
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spelling	oai:doaj.org-article:1310ff27dbfc4d2fb7b789a504b6712c2021-12-02T04:39:19ZAcute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice1178-2013https://doaj.org/article/1310ff27dbfc4d2fb7b789a504b6712c2019-02-01T00:00:00Zhttps://www.dovepress.com/acute-physiological-changes-caused-by-complement-activators-and-amphot-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Erik Őrfi,1,2 Tamás Mészáros,1,2 Mark Hennies,3 Tamás Fülöp,1,2 László Dézsi,1,2 Alexander Nardocci,1 László Rosivall,1,2 Péter Hamar,4,5 Barry W Neun,6 Marina A Dobrovolskaia,6 János Szebeni,1,2,7,* Gábor Szénási1,8,* 1Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; 2SeroScience LCC., Cambridge, MA, USA; 3TECOdevelopment GmbH, Rheinbach, Germany; 4Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary; 5Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; 6Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA; 7Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary; 8Institute of Pathophysiology, Semmelweis University, Budapest, Hungary *These authors contributed equally to this work 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. Keywords: hypersensitivity, infusion reactions, zymosan, cobra venom factor, TXB2, cholesterol, anaphylatoxins, plateletsŐrfi EMészáros THennies MFülöp TDézsi LNardocci ARosivall LHamar PNeun BWDobrovolskaia MASzebeni JSzénási GDove Medical PressarticleHypersensitivityinfusion reactionszymosancobra venom factorTXB2cholesterolanaphylatoxinsplateletsMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 1563-1573 (2019)

Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice

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