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

Erik Őrfi1,2, Tamás Mészáros1,2, Mark Hennies3

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Mice showed mild complement activation (C3a) and transient hypertension after AmBisome and Abelcet, suggesting mice can model C activation-related pseudoallergy (CARPA) to liposomal Amphotericin B.

Keywords:
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Area of Science:

  • Immunology
  • Nanomedicine
  • Pharmacology

Background:

  • Nanomedicines can trigger complement (C) activation, leading to C activation-related pseudoallergy (CARPA).
  • CARPA symptoms are documented in humans and several animal models, but data in mice are limited.
  • Amphotericin B nano-formulations like AmBisome and Abelcet carry a high risk of CARPA.

Purpose of the Study:

  • To investigate CARPA signs in mice following intravenous administration of AmBisome and Abelcet.
  • To assess the utility of mice as a model for studying CARPA induced by liposomal nanomedicines.

Main Methods:

  • Anesthetized mice received intravenous injections of liposomal amphotericin B (Abelcet, AmBisome), drug-free vesicles, cobra venom factor, or zymosan.
  • Measurements included blood pressure, heart rate, blood cell counts, plasma thromboxane B2, and C3a levels.
  • Complement activation was further assessed via C3 consumption and hemolytic assays.

Main Results:

  • Test agents, excluding drug-free vesicles, induced transient hypertension, thrombocytopenia, and elevated thromboxane B2.
  • Significant C3a rises and shock were observed with positive controls (CVF, zymosan).
  • AmBisome and Abelcet caused minor, delayed C3a increases without significant hypertension; a C3a receptor inhibitor partially reduced Abelcet-induced hypertension.

Conclusions:

  • The observed physiological changes correlate with C3a production, supporting CARPA as the underlying mechanism.
  • Despite higher liposomal phospholipid doses required compared to other species, mice appear suitable for studying hypersensitivity reactions to liposomal Amphotericin B.
  • This study provides valuable insights into CARPA mechanisms in mice, aiding the understanding of Amphotericin B side effects.