title: Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever.
abstract: Common formulations of amphotericin-B include a deoxycholate colloidal suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (l-Amph). The clinical incidence of infusion related fever is highest with d-Amph, intermediate with Ablc, and lowest with l-Amph. In the present study, we measured the activation of cyclooxygenase-2 (COX-2) and subsequent release of prostaglandin E-2 (PgE-2) from brain microvessel endothelium treated with these three formulations of amphotericin-B. Primary cultured bovine brain microvessel endothelial cells (BBMEC) were exposed to d-Amph, Ablc and l-Amph at concentrations that can be achieved in the plasma of patients receiving the drug. Media samples from the cells were collected and analyzed for PgE-2. Release of PgE-2 from BBMEC monolayers treated with l-Amph was similar to cells receiving culture media alone. In contrast, Ablc and d-Amph caused significantly greater release of PgE-2 from BBMEC monolayers compared to controls receiving culture media alone. PgE-2 release after d-Amph treatment was similar in magnitude to that observed with bacterial lipopolysaccharide (LPS). Western blot analysis indicated significant induction of COX-2 expression in BBMEC following LPS, Ablc or d-Amph treatment. Furthermore, PgE-2 release following exposure of BBMEC monolayers to either LPS or the various amphotericin-B formulations was reduced by the addition of the selective COX-2 inhibitor, NS-398. These studies indicate that amphotericin-B induces COX-2 expression in brain microvessel endothelium resulting in release of fever producing PgE-2. The magnitude of PgE-2 release from BBMEC following exposure to various amphotericin-B formulations mirrors the clinical observations regarding amphotericin-B induced fever and serves as initial support for the clinical use of COX-2 inhibitors to reduce amphotericin-B fever.
authors.affiliation: Department of Pharmacy Practice, University of Nebraska College of Pharmacy, 986045 Nebraska Medical Center, Omaha, NE 68198-6045, USA. trmcguir@unmc.edu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: McGuire
authors.forename: William J
authors.initials: WJ
authors.lastname: Trickler
authors.forename: Lynette
authors.initials: L
authors.lastname: Hock
authors.forename: Amy
authors.initials: A
authors.lastname: Vrana
authors.forename: Eric B
authors.initials: EB
authors.lastname: Hoie
authors.forename: Donald W
authors.initials: DW
authors.lastname: Miller
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply; D002417:Cattle; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005334:Fever / Q000139:chemically induced / Q000201:enzymology; D007527:Isoenzymes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008833:Microcirculation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*
chemical_list: D000935:Antifungal Agents; D017077:Culture Media, Conditioned; D007527:Isoenzymes; D008070:Lipopolysaccharides; D000666:Amphotericin B; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone