In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative

ABSTRACTThe present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency,in vitrodrug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellularLeishmania donovaniamastigotes,in vivopharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagicL. donovaniamastigotes. In thein vitrocell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs.In vivostudies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

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In vitro and in vivo resistance of Leishmania infantum to meglumine antimoniate: a study of 37 strains collected from patients with visceral leishmaniasis.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.4.827 ◽

1997 ◽

Vol 41 (4) ◽

pp. 827-830 ◽

Cited By ~ 140

Author(s):

F Faraut-Gambarelli ◽

R Piarroux ◽

M Deniau ◽

B Giusiano ◽

P Marty ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Strongly Correlated ◽

Duration Of Treatment ◽

In Vitro Sensitivity ◽

Sensitivity Tests ◽

Leishmania Parasites ◽

Immunocompetent Patients

Primary and secondary unresponsiveness to meglumine has long been described in human visceral leishmaniasis. However, no studies have been performed to elucidate if these therapeutic failures were due to strain variability in meglumine sensitivity or were related to host factors. We have studied the in vitro sensitivity of 37 strains of Leishmania infantum isolated from 23 patients (11 human immunodeficiency virus-infected and 12 immunocompetent patients) with visceral leishmaniasis. Sensitivity tests were performed by infecting murine macrophages with Leishmania parasites and culturing them in medium containing different concentrations of meglumine. For each test we calculated a 50% effective dose (ED50) corresponding to the meglumine concentration at which 50% of the Leishmania parasites survived. In vitro results were strongly correlated to immediate clinical outcome. All strains requiring an ED50 of >70 microg/ml were related to therapeutic failures, whereas all strains requiring an ED50 of <40 microg/ml corresponded to an initial efficiency of meglumine. Among those patients who were initially improved, relapses occurred in all immunocompromised patients and in most immunocompetent patients who had a short duration of treatment (15 days). Finally, we found that in vitro sensitivity of strains decreased progressively in relapsing patients treated with meglumine. Consequently, the physician may be encouraged to alternate meglumine with other treatments such as amphotericin B or pentamidine, especially in the case of relapsing patients.

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In Vitro Antileishmanial Activity of Nicotinamide

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.2.808-812.2005 ◽

2005 ◽

Vol 49 (2) ◽

pp. 808-812 ◽

Cited By ~ 35

Author(s):

D. Sereno ◽

A. Monte Alegre ◽

R. Silvestre ◽

B. Vergnes ◽

A. Ouaissi

Keyword(s):

Leishmania Major ◽

Growth Arrest ◽

Antileishmanial Activity ◽

Vitamin B ◽

Wild Type ◽

Intracellular Growth ◽

Cell Growth Arrest ◽

Transgenic Parasites

ABSTRACT Our study represents the first report demonstrating the antileishmanial activity of nicotinamide (NAm), a form of vitamin B3. A 5 mM concentration of NAm significantly inhibited the intracellular growth of Leishmania amastigotes and the NAD-dependent deacetylase activity carried by parasites overexpressing Leishmania major SIR2 (LmSIR2). However, the transgenic parasites were as susceptible as the wild-type parasites to NAm-induced cell growth arrest. Therefore, we conclude that NAm inhibits leishmanial growth and that overexpression of LmSIR2 does not overcome this inhibition. The mechanism of the inhibition is not defined but may include other in vivo targets. NAm may thus represent a new antileishmanial agent which could potentially be used in combination with other drugs during therapy.

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Oral administration of buparvaquone nanostructured lipid carrier enables in vivo activity against Leishmania infantum

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2021.106097 ◽

2021 ◽

pp. 106097

Author(s):

Lis Marie Monteiro ◽

Raimar Löbenberg ◽

Eduardo José Barbosa ◽

Gabriel Lima Barros de Araujo ◽

Paula Keiko Sato ◽

...

Keyword(s):

Oral Administration ◽

Leishmania Infantum ◽

Nanostructured Lipid Carrier

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