Activity of a Heat-Induced Reformulation of Amphotericin B Deoxycholate (Fungizone) against Leishmania donovani

ABSTRACT The heat treatment of amphotericin B deoxycholate (Fungizone), which was previously shown to induce superaggregation and decrease the toxicity of the drug to mammalian cells, increased its activity againstLeishmania donovani in BALB/c mice, whereas it reduced its toxicity. Heat treatment preserved the activity of Fungizone againstL. donovani HU3-infected mouse peritoneal macrophages.

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Fluorescence of Amphotericin B-Deoxycholate (Fungizone) Monomers and Aggregates and the Effect of Heat-Treatment

Langmuir ◽

10.1021/la7008573 ◽

2007 ◽

Vol 23 (17) ◽

pp. 8718-8725 ◽

Cited By ~ 17

Author(s):

Robin Stoodley ◽

Kishor M. Wasan ◽

Dan Bizzotto

Keyword(s):

Heat Treatment ◽

Amphotericin B ◽

Amphotericin B Deoxycholate

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Antileishmanial Activity of a Linalool-Rich Essential Oil from Croton cajucara

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.6.1895-1901.2003 ◽

2003 ◽

Vol 47 (6) ◽

pp. 1895-1901 ◽

Cited By ~ 141

Author(s):

Maria do Socorro S. Rosa ◽

Ricardo R. Mendonça-Filho ◽

Humberto R. Bizzo ◽

Igor de Almeida Rodrigues ◽

Rosangela Maria A. Soares ◽

...

Keyword(s):

Nitric Oxide ◽

Essential Oil ◽

Mammalian Cells ◽

Morphological Changes ◽

Peritoneal Macrophages ◽

Transmission Electron ◽

Low Concentrations ◽

Mouse Peritoneal Macrophages ◽

Croton Cajucara

ABSTRACT The in vitro leishmanicidal effects of a linalool-rich essential oil from the leaves of Croton cajucara against Leishmania amazonensis were investigated. Morphological changes in L. amazonensis promastigotes treated with 15 ng of essential oil per ml were observed by transmission electron microscopy; leishmanial nuclear and kinetoplast chromatin destruction, followed by cell lysis, was observed within 1 h. Pretreatment of mouse peritoneal macrophages with 15 ng of essential oil per ml reduced by 50% the interaction between these macrophages and L. amazonensis, with a concomitant increase by 220% in the level of nitric oxide production by the infected macrophages. Treatment of preinfected macrophages with 15 ng of essential oil per ml reduced by 50% the interaction between these cells and the parasites, which led to a 60% increase in the amount of nitric oxide produced by the preinfected macrophages. These results provide new perspectives on the development of drugs with activities against Leishmania, as linalool-rich essential oil is a strikingly potent leishmanicidal plant extract (50% lethal doses, 8.3 ng/ml for promastigotes and 8.7 ng/ml for amastigotes) which inhibited the growth of L. amazonensis promastigotes at very low concentrations (MIC, 85.0 pg/ml) and which presented no cytotoxic effects against mammalian cells.

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Action Of Ticlopidine On The Oxygenated Metabolism Of Arachidonic Acid In The Mouse Peritoneal Macrophages

10.1055/s-0038-1652498 ◽

1981 ◽

Author(s):

M Rigaud ◽

H Rabinovitch ◽

J Durand ◽

J C Breton ◽

G Rigaud

Keyword(s):

Arachidonic Acid ◽

Mammalian Cells ◽

Culture Medium ◽

Eicosatrienoic Acid ◽

Peritoneal Macrophages ◽

Membrane Phospholipids ◽

Glass Capillary ◽

Drug Concentrations ◽

High Concentrations ◽

Mouse Peritoneal Macrophages

When ticlopidine is added to macrophages cultures, in the absence of exogenous arachidonic acid, there is a production of both“prostanoids” and“eicosanoids” in the culture medium. These products have been measured using glass capillary gas chomatography prior to multiple ion mass spectrometry. The quantitative determinations are made 5, 15, 25, 35 and 45 minutes after the drug was added to the macrophages cultures. The three drug concentrations used (10-4M, 5.10-5M and 2.5 10-5M) induce a liberation of 6-keto-PGF1α in the culture medium. As in our system 6-keto-PGF1α seems to be the major metabolite of PGI2, ticlopidine is likely to act by releasing important quantities of PGI2 in macrophages. These results suggest an increase of liberation of the endogenous arachidonic acid from the membrane phospholipids of the macrophages or a lack in the acyltransferase system of the cell membranes. The lipoxygenasic pathway was also studied. When ticlopidine is added to macrophages, two products are liberated: . 12-HETE as measured by single iondetection . and 10-hydroxy-ll-12-epoxy, -5, 8, 14-eicosatrienoic acid which comes from an internal rearrangement of the 12-HPETE. In these results, there is a discrepancy between the fact that ticlopidine increases the concentration of 12-HETE and surely its precursor the 12-HPETE and the fact that the synthesis of PGI2 is not inhibited by these high concentrations of hydroperoxide. To understand this phenomenon we studied the production of hydroperoxide when arachidonic acid is incubated with soybean lipoxygenase. When ticlopidine (10-4M) is added to the reaction mixture (AA + soy lipoxygenase) there is an increase of the initial rate and an extent of the reaction as if the enzyme irreversible deactivation was postponed. Ticlopidine could act by suppressing the classical inhibition of PGI2 synthetase by hydroperoxides, in particular 12-HPETE and 15-HPETE, both produced by mammalian cells.

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Toxicity and Antileishmanial Activity of a New Stable Lipid Suspension of Amphotericin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.12.3774-3779.2003 ◽

2003 ◽

Vol 47 (12) ◽

pp. 3774-3779 ◽

Cited By ~ 46

Author(s):

Malika Larabi ◽

Vanessa Yardley ◽

Philippe M. Loiseau ◽

Martine Appel ◽

Philippe Legrand ◽

...

Keyword(s):

Amphotericin B ◽

Leishmania Donovani ◽

Lethal Dose ◽

Peritoneal Macrophages ◽

Lipid Complex ◽

Complex Formulation ◽

Cd1 Mice ◽

New Formulation ◽

Lipid Formulations

ABSTRACT The aim of the present study was to evaluate the toxicity and the activity of a new lipid complex formulation of amphotericin B (AMB) (LC-AMB; dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, and AMB) that can be produced by a simple process. Like other lipid formulations, this new complex reduced both the hemolytic activity of AMB (the concentration causing 50% hemolysis of human erythrocytes, >100 μg/ml) and its toxicity toward murine peritoneal macrophages (50% inhibitory concentration, >100 μg/ml at 24 h). The in vivo toxicity of the new formulation (50% lethal dose,> 200 mg/kg of body weight for CD1 mice) was similar to those of other commercial lipid formulations of AMB. The complex was the most effective formulation against the DD8 strain of Leishmania donovani. It was unable to reverse the resistance of an AMB-resistant L. donovani strain. In vivo LC-AMB was less efficient than AmBisome against L. donovani.

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Down-regulation of mannose receptors on macrophages after infection with Leishmania donovani

Biochemical Journal ◽

10.1042/bj2770451 ◽

1991 ◽

Vol 277 (2) ◽

pp. 451-456 ◽

Cited By ~ 34

Author(s):

N Basu ◽

R Sett ◽

P K Das

Keyword(s):

Leishmania Donovani ◽

Mannose Receptor ◽

Peritoneal Macrophages ◽

Receptor Activity ◽

Yeast Cells ◽

Surface Binding ◽

Infected Cells ◽

Receptor Number ◽

Mannose Receptors ◽

Mouse Peritoneal Macrophages

Macrophages express a mannose-specific endocytosis receptor that binds and internalizes mannose-terminated glycoproteins. Infection of mouse peritoneal macrophages with Leishmania donovani resulted in a decrease in mannose-receptor activity. With 125I-labelled beta-glucuronidase as ligand, a 2-fold decrease in uptake rate was observed in infected cells, with no change in Kuptake. Cell-surface binding of 125I-mannose-BSA was diminished 2.5-fold after infection. The decrease in ligand binding appeared to be due to a decrease in the number of sites, with no change in affinity. Elimination of parasites from infected cells by treatment with neoglycoprotein-conjugated methotrexate resulted in an increase in receptor number. Cycloheximide suppressed the drug-treatment-mediated rise in receptor number in infected macrophages. A decrease in receptor activity was also observed in liver Kupffer cells isolated from parasite-infected mice. Binding of ligand by another carbohydrate receptor, the mannose 6-phosphate receptor, was not altered by infection. Phagocytosis of yeast cells was also not altered. These results suggest that mannose receptor synthesis in macrophages is specifically suppressed after infection with Leishmania parasites.

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Heat-induced superaggregation of amphotericin B reduces its in vitro toxicity: a new way to improve its therapeutic index.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.11.2345 ◽

1997 ◽

Vol 41 (11) ◽

pp. 2345-2351 ◽

Cited By ~ 44

Author(s):

F Gaboriau ◽

M Chéron ◽

C Petit ◽

J Bolard

Keyword(s):

Heat Treatment ◽

Amphotericin B ◽

Mammalian Cells ◽

Therapeutic Index ◽

In Vitro Toxicity ◽

Thermal Pretreatment ◽

Colloidal Solutions ◽

Lactate Dehydrogenase Release ◽

Diphenyltetrazolium Bromide

Superaggregation of amphotericin B (AmB) was previously shown to occur upon heating of solutions at 70 degrees C. In the present study, we demonstrate that heat pretreatment of Fungizone (deoxycholate salt of AmB [AmB-DOC]) solutions induces a drastic decrease in the in vitro toxicity of this antibiotic. Heated AmB-DOC colloidal solutions, which mainly contained superaggregated and monomeric forms of the antibiotic, were strongly less hemolytic than unheated solutions (aggregates and monomers). Thermal pretreatment of AmB-DOC solutions also reduced the toxicity to the cell line HT29, as deduced from two simultaneous cell viability assays (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release). These heated colloidal solutions were only slightly less efficient than the unheated ones at inhibiting the growth of Candida albicans cells in vitro. Such results suggest that mild heat treatment of AmB-DOC solutions could provide a new and simple solution for improving the therapeutic index of this antifungal agent by reducing its toxicity to mammalian cells.

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