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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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-02-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/acute-physiological-changes-caused-by-complement-activators-and-amphot-peer-reviewed-article-IJN |
| _version_ | 1818744006525321216 |
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| 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 |
| collection | DOAJ |
| 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 |
| first_indexed | 2024-12-18T02:37:27Z |
| format | Article |
| id | doaj.art-1310ff27dbfc4d2fb7b789a504b6712c |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-18T02:37:27Z |
| publishDate | 2019-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-1310ff27dbfc4d2fb7b789a504b6712c2022-12-21T21:23:44ZengDove Medical PressInternational Journal of Nanomedicine1178-20132019-02-01Volume 141563157344312Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in miceŐrfi EMészáros THennies MFülöp TDézsi LNardocci ARosivall LHamar PNeun BWDobrovolskaia MASzebeni JSzénási GErik 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, plateletshttps://www.dovepress.com/acute-physiological-changes-caused-by-complement-activators-and-amphot-peer-reviewed-article-IJNHypersensitivityinfusion reactionszymosancobra venom factorTXB2cholesterolanaphylatoxinsplatelets |
| spellingShingle | 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 International Journal of Nanomedicine Hypersensitivity infusion reactions zymosan cobra venom factor TXB2 cholesterol anaphylatoxins platelets |
| 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 | Hypersensitivity infusion reactions zymosan cobra venom factor TXB2 cholesterol anaphylatoxins platelets |
| url | https://www.dovepress.com/acute-physiological-changes-caused-by-complement-activators-and-amphot-peer-reviewed-article-IJN |
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