Amphotericin B Kills Unicellular Leishmanias by Forming Aqueous Pores Permeable to Small Cations and Anions

Ramos, H.; Valdivieso, Elizabeth; Gamargo, M.; Dagger, Fracehuli; Cohen, Benjamin E.

doi:10.1007/s002329900086

Cited by 122 publications

(74 citation statements)

References 24 publications

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“…The toxicity induced by AMB is now believed to involve several different mechanisms: cell membrane permeability due to complexes formed between the antibiotic and sterol (5) and lipid peroxidation induced by the auto-oxidation of antibiotic (3,6). Similar mechanisms of toxicity against Leishmania have been shown (8,33,34).…”

Section: Discussionsupporting

confidence: 68%

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: Discussionsupporting

confidence: 68%

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 most recognized mechanism is the formation of pores in the cell membrane. Increased membrane permeability causes leakage of small molecules (1,3,8,22,24). The primary action site of AMB on fungal cells is believed to be the membrane component, ergosterol.…”

Section: Vol 46 2002 Cmt-3 a New Chemically Modified Tetracyclinementioning

confidence: 99%

A Chemically Modified Tetracycline (CMT-3) Is a New Antifungal Agent

Liu

Ryan

Lee

et al. 2002

Antimicrob Agents Chemother

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Several chemically modified tetracycline analogs (CMTs), which were chemically modified to eliminate their antibacterial efficacy, were unexpectedly found to have antifungal properties. Of 10 CMTs screened in vitro, all exhibited antifungal activities, although their efficacies varied. Among these compounds, CMT-315, -3, and -308 were found to be the most potent as antifungal agents. The MICs of CMT-3 against 47 strains of fungi in vitro were determined by using amphotericin B (AMB) and doxycycline as positive and negative controls, respectively. The MICs of CMT-3 were generally found to be between 0.25 and 8.00 g/ml, a range that approximates the blood levels of this drug when administrated orally to humans. Of all the yeast species tested to date, Candida albicans showed the greatest sensitivity to CMT-3. The filamentous species most susceptible to CMT-3 were found to be Epidermophyton floccosum, Microsporum gypseum, Pseudallescheria boydii, a Penicillium sp., Scedosporium apiospermum, a Tricothecium sp., and Trichophyton rubrum. Growth inhibition of C. albicans by CMT-3, determined by a turbidity assay, indicated a 50% inhibitory concentration of 1 g/ml. Thirty-nine strains, including 20 yeasts and 19 molds, were used to measure viability (the ability to grow after treatment with a drug) inhibition by CMT-3 and AMB. CMT-3 exhibited fungicidal activity against most of these fungi, especially the filamentous fungi. Eighty-four percent (16 of 19) of the filamentous fungi tested showed more than 90% inhibition of viability by CMT-3. In contrast, AMB showed fungicidal activity against all yeasts tested. However, most of the filamentous fungi (16 of 19) showed less than 50% inhibition of viability by AMB, indicating that AMB is fungistatic against most of these filamentous fungi. To begin to identify the sites in fungal cells affected by CMT-3, C. albicans and a Penicillium sp. were incubated with the compound at 35°C, and then the fluorescence of CMT-3 was observed by confocal laser scanning electron microscopy. CMT-3 appeared to have widespread intracellular distribution throughout C. albicans and the Penicillium sp. The mechanisms of the antifungal activity of CMT-3 are now being explored.

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“…The mechanism of action is based on the high affinity of amphotericin B to ergosterol, the prevalent sterol in the plasma membrane of the parasite. It is thought that amphotericin B forms aqueous pores within the plasma membrane (26,27). As a result, permeability to monovalent cations and small metabolites increases.…”

Section: Disease and Clinical Manifestationsmentioning

confidence: 99%

“…Several quinovic acid glycosides [21][22][23][24][25][26][27][28][29] isolated from Nauclea diderrichii (Rubiaceae) exert in vitro anti-leishmanial activity against L. infantum with IC 50 values between 1.1 and 85 μM against intracellular amastigotes (Fig. 4).…”

Section: Quinoline Alkaloids 2-substituted Quinolines Isolated Frommentioning

confidence: 99%

Leishmaniasis: Drug resistance and natural products (Review)

Polonio

Efferth²

1998

Int J Mol Med

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Abstract. Epidemics of fatal visceral leishmaniasis caused by the intracellular protozoan Leishmania are a severe public health problem in tropical and subtropical regions of the world. One major drawback in the treatment of leishmaniasis is the emergence of resistance to current chemotherapeutics. Leishmanicidals have to be administered in low doses since commonly used drugs exhibit severe side effects, and hence drug resistance can appear rapidly. Since, to date, vaccination approaches have failed to enter clinical trials, chemotherapy based on small molecules is temporarily the exclusive treatment strategy. There is an urgent need for adding novel drugs with improved features to the pool of current chemotherapeutics. Many compounds derived from natural sources have pharmacological activities and may, thus, be of potential utility in drug development and biomedical research. Natural products, primarily plant-derived substances of diverse structural classes, have been described in the literature showing anti-leishmanial properties. In this review we provide a brief overview of the current treatment and the active principles of established drugs. Furthermore, we focus on the mechanisms of drug resistance and natural products that are promising leads for the development of novel chemotherapeutics.

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Amphotericin B Kills Unicellular Leishmanias by Forming Aqueous Pores Permeable to Small Cations and Anions

Cited by 122 publications

References 24 publications

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB

A Chemically Modified Tetracycline (CMT-3) Is a New Antifungal Agent

Leishmaniasis: Drug resistance and natural products (Review)

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