Cytokine antibody arrays were used to establish the profiles of cytokine release from THP-1 monocytes exposed to different amphotericin B (AMB) drug delivery systems. Fungizone (FZ) and Amphotec (ABCD) caused the release of significantly more inflammatory molecules and the release of inflammatory molecules at higher levels than either AmBisome (L-AMB) or Abelcet (ABLC) after 6 h of treatment. Specifically, tumor necrosis factor alpha (TNF-␣), interleukin-8 (IL-8), GRO-(␣␥), monocyte chemoattractant protein-1 (MCP-1), RANTES, IL-10, and IL-6 were detected and semiquantified with a chemiluminscence imaging system. TNF-␣, IL-8, and MCP-1 were the most predominant; however, little if any TNF-␣ was present in ABLC-or L-AMB-treated cultures. The TNF-␣ and IL-8 levels determined by quantitative enzyme-linked immunosorbent assay correlated with the relative cytokine levels measured by using the antibody arrays. Although the viabilities of THP-l monocytes in all AMB-treated cultures were similar by trypan blue exclusion, the amount of lactic dehydrogenase released was significantly larger in FZ-and ABCD-treated cultures than in L-AMBand ABLC-treated cultures, indicating more membrane perturbations with those formulations. Membrane cation channel formation was also measured in model cholesterol-containing large unilamellar vesicles to directly assess the ion channel formation ability of the system. Only FZ and ABCD induced significant ion currents at concentrations less than 1.5 ؋ 10 ؊5 M. These results may help provide rationales for the immediate cytokine-mediated side effects observed with FZ and ABCD and the reduced side effects observed with L-AMB and ABLC.Amphotericin B (AMB) is a polyene antifungal antibiotic and for a number of years has been the "gold standard" for the treatment of systemic fungal infections. Three new lipid-based formulations, Abelcet (ABLC), Ambisome (L-AMB), and Amphotec (ABCD), have been developed in an attempt to obtain improved efficacies, therapeutic indices, and tolerabilities compared to those of the traditional AMB formulation, Fungizone (FZ). In clinical trials, improvements in renal tolerability were shown for all three lipid formulations; however, the levels of acute toxicity, including fever, chills, hypotension, and nausea, vary with each formulation (8, 23). L-AMB has been shown to promote the least adverse effects, while immediate reactions to ABCD are often as frequent and severe as those to FZ (23). Clinical toxicity has been associated with increases in plasma tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) levels during infusion of the drug (1), while in vitro studies with the human THP-1 monocytic cell line have further identified and characterized a number of proinflammatory cytokines that are induced and released following exposure to FZ (5,19,20). Because the clinical effects of the four AMB formulations are different, we hypothesized that each AMB formulation would produce a different cytokine profile. Using recently developed antibody arrays (13, 27) and t...
