Reduction of NO Synthase Expression and Tumor Necrosis Factor Alpha Production in Macrophages by Amphotericin B Lipid Carriers

Larabi, Malika; Legrand, Philippe; Appel, M.; Gil, Sophie; Lepoivre, Michel; Devissaguet, Jean‐Philippe; Puisieux, F.; Barratt, Gillian

doi:10.1128/aac.45.2.553-562.2001

Cited by 22 publications

(14 citation statements)

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“…In previous work, we compared the association of different AMB formulations with mouse peritoneal macrophages (21). This was much greater for the commercial complexes Amphotec and Abelcet than for the liposomes (AmBisome, Ampholiposomes), with the association of LC-AMB intermediate between those of these two groups.…”

Section: Discussionmentioning

confidence: 99%

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

Larabi¹,

Yardley²,

Loiseau

et al. 2003

Antimicrob Agents Chemother

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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 g/ml) and its toxicity toward murine peritoneal macrophages (50% inhibitory concentration, >100 g/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 AMBresistant L. donovani strain. In vivo LC-AMB was less efficient than AmBisome against L. donovani.There is a need for a new treatment for patients with visceral leishmaniasis (VL), particularly those with AIDS, since there is a high incidence of relapse after treatment with pentavalent antimonial drugs (11,19,25,32). Despite the recent success with miltefosine as an antileishmanial drug (17, 36), its use is limited because of the risk of the rapid development of resistance if it is used alone (7). The antifungal drug amphotericin B (AMB), a polyene antibiotic, is commonly used to treat leishmaniasis, but its application is limited because of its acute toxicity, which leads to a low therapeutic index when it is used as the traditional formulation, Fungizone (i.e., micelles mixed with the detergent deoxycholate) (18). In order to reduce this dose-limiting toxicity, different commercial lipid-based formulations have been developed and used in the clinical management of VL: AmBisome (4, 10), Abelcet (38, 39), and Amphotec (12). These have also been used as alternative treatments for mucocutaneous leishmaniasis (35,46). In some developed countries, AmBisome is now indicated as the first-line therapy against VL. However, the high prices of these formulations restrict their use in the regions most affected by these tropical diseases (24,15).Recently, several less expensive AMB formulations have been tested. Such formulations include the AMB derivatives prepared and described by Al-Abdely et al. (1) and Golenser et al. (14), which are water soluble and also less toxic. Heat treatment of Fungizone is an inexpensive technique for reduction of its toxicity (31), as is extemporaneous mixing of Fungizone with Intralipid (20, 40). Another particulate formulation with anionic lipids is stable and has good in vitro and in vivo efficacies (26). However, AmBisome remains the most effective formulation for the treatment of VL (46), and none of these formulations has yet been proved to be more active than the commercial ones.The present study was designed to evaluate the antileishmanial activity of a new lipid formulation of AMB in comparison with those of other commercially available lipid-AMB formula...

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Section: Discussionmentioning

confidence: 99%

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

Larabi¹,

Yardley²,

Loiseau

et al. 2003

Antimicrob Agents Chemother

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“…Moreover, it has been previously reported that the association of AmB with poly(1-caprolactone) nanospheres decreased the acute toxicity of the polyene in mice (Espuelas et al, 1997). Also, we evaluated the possibility of an indirect antileishmanial activity of nanoparticles themselves (Gaspar et al, 1992;Vernier-Julienne et al, 1995) or even AmB-mediated (Mozaffarian et al, 1997;Larabi et al, 2001) through macrophage activation for cytokines and oxygen derivatives production.…”

Section: Introductionmentioning

confidence: 97%

In Vitro Antileishmanial Activity of Amphotericin B Loaded in Poly(ε-Caprolactone) Nanospheres

Espuelas

Legrand

Loiseau

et al. 2002

Journal of Drug Targeting

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The activity of formulations for amphotericin B (AmB) associated with poly(epsilon-caprolactone) nanospheres and coated with variable amounts of a non ionic surfactant poloxamer 188, was evaluated against AmB-susceptible (WT) and AmB-resistant (AmB(r)) strains of Leishmania donovani amastigotes in thioglycolate-elicited peritoneal macrophages. AmB-nanospheres were more actives than free AmB only against amastigotes of wild strain. The activity was not influenced by the concentration of poloxamer 188 used to stabilize the nanospheres in spite of this surfactant was previously reported to synergy with AmB on the membrane of the resistant parasite. Similarly, this improvement was not mediated through macrophage activation. In fact, these nanoparticle formulations appeared to inhibit both NO and TNF-alpha production induced by the free drug. Therefore, we suggest that the association of AmB with nanospheres may improve the capability of the drug to interact with ergosterol. This hypothesis appears to be supported by the fact that nanospheres did not show any improvement of the AmB activity against the resistant strain (characterized by the absence of ergosterol).

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“…Liposomal formulations of AmB reduce the toxicities observed with free AmB. However, it is also possible that different lipid-associated formulations of AmB may modify the immunomodulatory activity of the drug (31,32), thus masking the beneficial immunomodulatory properties of AmB. Despite its high cost, liposomal AmB (AmBisome) remains the best antileishmanial formulation for the treatment of VL (33).…”

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confidence: 99%

Complete Cure of Experimental Visceral Leishmaniasis with Amphotericin B in Stearylamine-Bearing Cationic Liposomes Involves Down-Regulation of IL-10 and Favorable T Cell Responses

Banerjee

Ali

2008

The Journal of Immunology

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Visceral leishmaniasis caused by Leishmania donovani is a life-threatening disease involving uncontrolled parasitization of liver, spleen, and bone marrow. Most available drugs are toxic. Moreover, relapse after seemingly successful therapy remains a chronic problem. In this study, we evaluated a new therapeutic approach based on combination of a low dose of amphotericin B (AmB) in association with suboptimum dose of stearylamine (SA)-bearing cationic liposomes, itself having leishmanicidal activity. We demonstrate that a single-shot therapy with this formulation caused clearance of parasites from liver and spleen below the level of detection in the selected piece of the organs of BALB/c mice. The combination was superior to free AmB and AmBisome for therapy, as well as for prevention of relapse and reinfection. Besides having better killing activity, AmB in SA liposomes, in contrast to AmBisome, maintained the immunomodulatory effect of free AmB on CD4+ and CD8+ T cells for IFN-γ production, at the same time reducing the toxic effects of the drug, reflected through decline in TNF-α. In addition, IL-10 was down-regulated to almost negligible levels, most efficiently through therapy with SA-bearing cationic liposomes-AmB. This IL-10-deficient environment of IFN-γ-secreting T cells probably up-regulated the enhanced IL-12 and NO production observed in splenic culture supernatants of these mice, correlating with prolonged disease suppression better than free AmB and AmBisome. The ability of the formulation to elicit protective immunity was reconfirmed in a prophylactic model. Our results emphasize the requirement of effective immune stimulation, additionally, by antileishmanials for persistent disease protection, demonstrated by this liposomal AmB formulation.

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Reduction of NO Synthase Expression and Tumor Necrosis Factor Alpha Production in Macrophages by Amphotericin B Lipid Carriers

Cited by 22 publications

References 50 publications

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

In Vitro Antileishmanial Activity of Amphotericin B Loaded in Poly(ε-Caprolactone) Nanospheres

Complete Cure of Experimental Visceral Leishmaniasis with Amphotericin B in Stearylamine-Bearing Cationic Liposomes Involves Down-Regulation of IL-10 and Favorable T Cell Responses

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