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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... Full description

Journal Title: International Journal of Nanomedicine 2019, Vol.14, pp.1563-1573
Main Author: Őrfi, Erik
Other Authors: Mészáros, Tamás , Hennies, Mark , Fülöp, Tamás , Dézsi, László , Nardocci, Alexander , Rosivall, László , Hamar, Péter , Neun, Barry , Dobrovolskaia, Marina , Szebeni, János , Szénási, Gábor
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1176-9114 ; E-ISSN: 1178-2013 ; DOI: 10.2147/IJN.S187139
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title: Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
format: Article
creator:
  • Őrfi, Erik
  • Mészáros, Tamás
  • Hennies, Mark
  • Fülöp, Tamás
  • Dézsi, László
  • Nardocci, Alexander
  • Rosivall, László
  • Hamar, Péter
  • Neun, Barry
  • Dobrovolskaia, Marina
  • Szebeni, János
  • Szénási, Gábor
subjects:
  • Hungary
  • United States–Us
  • Germany
  • Laboratories
  • Veins & Arteries
  • Lipids
  • Blood Pressure
  • Experiments
  • Medical Research
  • Heart Rate
  • Statistical Analysis
  • Hypersensitivity
  • Infusion Reactions
  • Zymosan
  • Cobra Venom Factor
  • Txb2
  • Cholesterol
  • Anaphylatoxins
  • Platelets
ispartof: International Journal of Nanomedicine, 2019, Vol.14, pp.1563-1573
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.
language: eng
source:
identifier: ISSN: 1176-9114 ; E-ISSN: 1178-2013 ; DOI: 10.2147/IJN.S187139
fulltext: fulltext_linktorsrc
issn:
  • 11769114
  • 1176-9114
  • 11782013
  • 1178-2013
url: Link


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titleAcute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
creatorŐrfi, Erik ; Mészáros, Tamás ; Hennies, Mark ; Fülöp, Tamás ; Dézsi, László ; Nardocci, Alexander ; Rosivall, László ; Hamar, Péter ; Neun, Barry ; Dobrovolskaia, Marina ; Szebeni, János ; Szénási, Gábor
ispartofInternational Journal of Nanomedicine, 2019, Vol.14, pp.1563-1573
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subjectHungary ; United States–Us ; Germany ; Laboratories ; Veins & Arteries ; Lipids ; Blood Pressure ; Experiments ; Medical Research ; Heart Rate ; Statistical Analysis ; Hypersensitivity ; Infusion Reactions ; Zymosan ; Cobra Venom Factor ; Txb2 ; Cholesterol ; Anaphylatoxins ; Platelets
descriptionPurpose: 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.
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titleAcute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
descriptionPurpose: 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.
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titleAcute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice
authorŐrfi, Erik ; Mészáros, Tamás ; Hennies, Mark ; Fülöp, Tamás ; Dézsi, László ; Nardocci, Alexander ; Rosivall, László ; Hamar, Péter ; Neun, Barry ; Dobrovolskaia, Marina ; Szebeni, János ; Szénási, Gábor
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abstractPurpose: 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.
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