Lipid complexing decreases amphotericin B inflammatory activation of human neutrophils compared with that of a desoxycholate-suspended preparation of amphotericin B (Fungizone)

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a second stimulus. AmB also stimulates mononuclear leukocytes (MNLs) to release inflammatory mediators which augment the effects of AmB on PMN function. In the present study, we observed that the methylxanthine derivative pentoxifylline decreased the effects of AmB on PMN function. AmB (2 ,ug/ml) priming doubled PMN chemiluminescence stimulated by fMet-Leu-Phe. In the presence of MNLs, AmB priming increasedjMet-Leu-Phe-stimulated PMN chemiluminescence to 622% of unprimed PMN activity. Pentoxifylline (100 ,uM) blunted the rise in AmB-augmented PMN chemiluminescence in the presence of MNLs to 282% of unprimed PMN activity, and pentoxifylline metabolites were active at 10 ,IM. Pentoxifylline (100 ,uM) also blocked AmB-augmented PMN oxidative activity in whole blood, as measured by nitroblue tetrazolium reduction. In the presence of MNL, AmB (2 ,ug/ml) doubled the expression of the important PMN adherence factor Mac-1. Pentoxifylline (1 mM) decreased AmB-stimulated PMN Mac-i expression back to unstimulated amounts. In the presence of MNLs, AmB (2 jig/ml) decreased PMN nondirected and directed migration to fMet-Leu-Phe to 40 and 38% of control PMN migration, respectively. Pentoxifylline (300 ,uM) counteracted AmB inhibition of nondirected and directed migration to fMet-Leu-Phe, resulting in migration that was 71 and 87% of control PMN migration, respectively. In contrast, the methylxanthine caffeine (100 ,iM) increased AmB-enhanced chemiluminescence but did not affect AmBinhibited PMN migration. Pentoxifylline should be evaluated as adjunctive therapy to lessen the inflammatory damage caused by AmB.The antifungal agent amphotericin B (AmB) has a stimulatory effect on several polymorphonuclear leukocyte (PMN) functions. AmB increases PMN adherence to nylon wool, PMN aggregation (5,9,10,35,40,69), and PMN oxidative activity (59). AmB also activates macrophages (15,34,48,66,67) and induces the production of tumor necrosis factor alpha (TNF-ot) and interleukin-1 beta 8) (17,25). We have observed that the presence of mononuclear leukocytes (MNLs) exacerbates the inflammatory effects of AmB on PMN function, including AmB priming of the PMN oxidative burst and PMN expression of the adherence inte-

Section: Resultsmentioning

confidence: 86%

mentioning

confidence: 99%

Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro

Sullivan

Carper

Mandell

1992

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“…While the reported effects of amphotericin B formulations on O 2 Ϫ production by human phagocytes have been contradictory (18,22,25,26), in the present study none of the amphotericin B formulations affected O 2 Ϫ production from pretreated MNCs in response to either nonopsonized or serum-opsonized A. fumigatus hyphae. The exception was the ABLC-treated MNCs, which at the high concentration of ABLC, 25 g/ml, significantly reduced the production of O 2 Ϫ in response to serum-opsonized A. fumigatus hyphae.…”

Section: Discussionmentioning

confidence: 39%

“…Specifically, DAMB and ABLC were found to additively augment the fungicidal activity of pulmonary alveolar macrophages against conidia of A. fumigatus (17). However, the studies of the effects of DAMB on oxidative burst of phagocytes as evidenced by O 2 Ϫ production have shown contradictory results (18,22,25,26). To date, there are no reports published on the comparative effects of the four formulations on the antifungal activity of monocytes (MNCs) against A. fumigatus.…”

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confidence: 97%

Effects of Lipid Formulations of Amphotericin B on Activity of Human Monocytes against Aspergillus fumigatus

Dotis

Simitsopoulou

Dalakiouridou

et al. 2006

Invasive aspergillosis is the most frequent opportunistic filamentous fungal infection causing excessive morbidity and mortality in immunocompromised patients (9, 12). Mononuclear phagocytes constitute a prominent component of the host defense against Aspergillus spp. (24). In particular, NADP (NADPH)-dependent production of antifungal compounds, such as superoxide anion (O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), and H 2 O 2 -dependent intracellular intermediates (DIIs), contributes to phagocyte-induced damage of microorganisms including fungi (2,8,16). While O 2 Ϫ production is an early event of oxidative burst, H 2 O 2 and DIIs consisting of compounds such as hydroxyl radical and HOCl are produced at late steps and are even more powerful oxidizing species.For decades, deoxycholate amphotericin B (DAMB) has been considered to be the cornerstone of antifungal therapy for fungal infections including invasive aspergillosis (1, 21). However, due to frequent infusion-related reactions and doselimiting nephrotoxicity, less-toxic lipid-associated formulations, such as liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD), have been developed (5,7,15). These compounds appear to offer a better therapeutic index than DAMB, circumscribing excessive toxicity (5, 7). Although newer azoles and echinocandins have been added to the antifungal armamentarium, amphotericin B formulations remain important agents against invasive aspergillosis.While lipid formulations of amphotericin B differ in their degree of induction of infusion-related reactions, little is known about their immunomodulatory effects when each of them is combined with phagocytes against Aspergillus fumigatus. Specifically, DAMB and ABLC were found to additively augment the fungicidal activity of pulmonary alveolar macrophages against conidia of A. fumigatus (17). However, the studies of the effects of DAMB on oxidative burst of phagocytes as evidenced by O 2 Ϫ production have shown contradictory results (18,22,25,26). To date, there are no reports published on the comparative effects of the four formulations on the antifungal activity of monocytes (MNCs) against A. fumigatus. We therefore investigated whether DAMB, LAMB, ABLC, and ABCD enhance the antifungal activities of monocytes against hyphae of A. fumigatus, as evidenced by monocyte-mediated hyphal damage, production of O 2 Ϫ , and production of H 2 O 2 as well as secondary DIIs, both in response to A. fumigatus.

“…Furthermore, it enhances the killing abilities of PMNs or macrophages (2, 5, 15, 19, 31, 33, 37-39, 41, 42, 47, 52, 59, 61, 65). The ability of amphotericin B to increase the activities of PMNs and macrophages may be the reason for its inflammatory properties (52,53). The allylamines (naftifine and terbinafine), a new generation of broad-spectrum antimycotic compounds, have recently been developed; they act by interfering with squalene 2,3-epoxidase, which results in decreased amounts of the principal membrane sterols, especially ergosterol (44,48).…”

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confidence: 99%

Effects of naftifine and terbinafine, two allylamine antifungal drugs, on selected functions of human polymorphonuclear leukocytes

Vago

Baldi

Colombo

et al. 1994

Many antimycotic agents negatively affect the natural immune response. Typically, these drugs impair polymorphonuclear leukocyte (PMN) production of superoxide anion, chemotaxis, or the killing of pathogens.Allylamines are a new class of antimycotic compounds with a new mechanism of antifungal action, i.e., inhibition of the fungal squalene epoxidase. The trial that we describe aimed to evaluate the effects of two allylamines, terbinafine and naftifine, on selected functions of PMNs, i.e., superoxide anion production, chemotaxis, and killing of Candida albicans blastospores. Terbinafine and naftifine on their own did not affect superoxide anion production when they were added to PMNs. When PMNs were preincubated with allylamines and were then stimulated by N-formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate, superoxide anion production was increased (priming effect). Since intracellular free calcium (Ca2 ,) is involved in the control of superoxide anion production, we evaluated the effects of the allylamines on the Ca2+i concentration ([Ca2+] i).In the presence of terbinafine or naftifine, the [Ca2+]i increased in a dose-dependent manner, the source of Ca2 i was not extracellular since it was not affected by extracellular calcium chelation with ethylene