Pharmacokinetic of meglumine antimoniate encapsulated in phosphatidylserine-liposomes in mice model: A candidate formulation for visceral leishmaniasis

Borborema, Samanta Etel Treiger; Osso, João Alberto; Tempone, André G.; Andrade, Heitor Franco de; Nascimento, N.

doi:10.1016/j.biopha.2018.05.004

Cited by 15 publications

(14 citation statements)

References 40 publications

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“…This improved reduction of parasites could be ascribed to a superior uptake of the PS-liposomes by the liver. A biodistribution study of PS-liposomes containing pentavalent antimony in Leishmania infantum -infected mice, demonstrated a slow clearance of the drug in the liver, resulting in sustained levels of the drug after administration [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting intracellular Leishmania (L.) infantum with nitazoxanide entrapped into phosphatidylserine-nanoliposomes: An experimental study

Pinto

Barbosa

Mortara

et al. 2020

Chemico-Biological Interactions

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Leishmaniasis is a parasitic neglected tropical disease and result in a broad spectrum of clinical manifestations, ranging from a single ulceration to a progressive and fatal visceral disease. Comprising a limited and highly toxic therapeutic arsenal, new treatments are urgently needed. Targeting delivery of drugs has been a promising approach for visceral leishmaniasis (VL). Phosphatidylserine-liposomes have demonstrated superior efficacy in VL, targeting intracellular parasites in host cells through macrophage scavenger receptors. In this work, we investigated the in vitro and in vivo efficacy of the antihelminthic drug nitazoxanide in a nanoliposomal formulation against Leishmania ( L. ) infantum . Physicochemical parameters of liposomes containing nitazoxanide (NTZ-LP) were determined by dynamic light scattering and small angle X-ray scattering. The efficacy of the formulation was verified in an intracellular amastigote model and in an experimental hamster model. Our findings showed that NTZ-LP was able to eliminate the amastigotes inside the host cell with an IC 50 value of 16 μM. NTZ-LP was labelled a fluorescent probe and by spectrofluorimetry, we observed that the infected macrophages internalized similar levels of the drug to the uninfected cells. The confocal microscopy images confirmed the uptake and demonstrated a diffuse distribution of the NTZ-LP in the cytoplasm of Leishmania -infected macrophages, with the vesicles in a closer proximity to the parasites. For the in vivo efficacy, the liposomal NTZ-LP was administrated intraperitoneally to Leishmania -infected hamsters for 10 consecutive days at 2 mg/kg/day. By qPCR we demonstrated a reduction of the parasite burden by 82% and 50% in the liver (p < 0.05) and spleen (p < 0.05), respectively. NTZ (non-liposomal) was administered at 100 mg/kg/day per oral (p.o.) for the same period, but demonstrated no efficacy. This liposomal formulation ensured a targeting delivery of NTZ to the intracellular parasites, resulting in an good efficacy at a low dose in animals, and it may represent a new candidate therapy for VL.

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Section: Discussionmentioning

confidence: 99%

Targeting intracellular Leishmania (L.) infantum with nitazoxanide entrapped into phosphatidylserine-nanoliposomes: An experimental study

Pinto

Barbosa

Mortara

et al. 2020

Chemico-Biological Interactions

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“…Two experimental groups of mice (22 ± 1 g) were used: (i) L. ( L. ) amazonensis -infected mice (n=40) and (ii) uninfected mice (n=40). The biodistribution of MA in uninfected animals previously reported by our research group [21,22] was utilized in the present study for comparison with that of infected animals. In each group, eight subgroups of five animals were randomly distributed.…”

Section: Methodsmentioning

confidence: 99%

“…It is important to know whether the infection can change the biodistribution pattern of a drug. Therefore, in continuation of the investigation of MA pharmacokinetic properties [21,22], the current study was undertaken to investigate its pharmacokinetic profile in Leishmania ( Leishmania ) amazonensis -infected mouse model using a radiotracer approach.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

Borborema

Osso

Andrade

et al. 2019

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: Cutaneous leishmaniasis (CL) is a parasitic disease caused by the protozoan Leishmania spp. Pentavalent antimonial agents have been used as an effective therapy, despite their side effects and resistant cases. Their pharmacokinetics remain largely unexplored. This study aimed to investigate the pharmacokinetic profile of meglumine antimoniate in a murine model of cutaneous leishmaniasis using a radiotracer approach. Methods: Meglumine antimoniate was neutron-irradiated inside a nuclear reactor and was administered once intraperitoneally to uninfected and L . amazonensis -infected BALB/c mice. Different organs and tissues were collected and the total antimony was measured. Results: Higher antimony levels were found in infected than uninfected footpad (0.29% IA vs. 0.14% IA, p = 0.0057) and maintained the concentration. The animals accumulated and retained antimony in the liver, which cleared slowly. The kidney and intestinal uptake data support the hypothesis that antimony has two elimination pathways, first through renal excretion, followed by biliary excretion. Both processes demonstrated a biphasic elimination profile classified as fast and slow. In the blood, antimony followed a biexponential open model. Infected mice showed a lower maximum concentration (6.2% IA/mL vs. 11.8% IA/mL, p = 0.0001), a 2.5-fold smaller area under the curve, a 2.7-fold reduction in the mean residence time, and a 2.5-fold higher clearance rate when compared to the uninfected mice. Conclusions: neutron-irradiated meglumine antimoniate concentrates in infected footpad, while the infection affects antimony pharmacokinetics.

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“…Regarding VL disease, many different DDS have been reported to target the drug to Leishmani a-infected organs, reducing the parasitic load and enhancing the therapeutic outcome [ 21 ]. Liposomes are considered appropriate carriers to treat VL for their natural tendency to be taken up by the mononuclear phagocyte system, namely by macrophages which are the cells where Leishmania parasite resides [ 22 ]. For many years, Amphotericin B has been used in clinical therapy for leishmaniasis in the form of a safe liposomal formulation known as AmBisome ® [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…For many years, Amphotericin B has been used in clinical therapy for leishmaniasis in the form of a safe liposomal formulation known as AmBisome ® [ 23 ]. Moreover, promising approaches have been done in VL with other antileishmanial drugs like meglumine antimoniate [ 22 , 24 ] or paromomycin [ 25 ] encapsulated in liposomes.…”

Section: Introductionmentioning

confidence: 99%

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

et al. 2020

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Berberine (BER)—an anti-inflammatory quaternary isoquinoline alkaloid extracted from plants—has been reported to have a variety of biologic properties, including antileishmanial activity. This work addresses the preparation of BER-loaded liposomes with the aim to prevent its rapid liver metabolism and improve the drug selective delivery to the infected organs in visceral leishmaniasis (VL). BER liposomes (LP-BER) displayed a mean size of 120 nm, negative Z-potential of −38 mV and loaded 6 nmol/μmol lipid. In vitro, the loading of BER in liposomes enhanced its selectivity index more than 7-fold by decreasing its cytotoxicity to macrophages. In mice, LP-BER enhanced drug accumulation in the liver and the spleen. Consequently, the liposomal delivery of the drug reduced parasite burden in the liver and spleen by three and one logarithms (99.2 and 93.5%), whereas the free drug only decreased the infection in the liver by 1-log. The organ drug concentrations—far from IC50 values— indicate that BER immunomodulatory activity or drug metabolites also contribute to the efficacy. Although LP-BER decreased 10-fold—an extremely rapid clearance of the free drug in mice—the value remains very high. Moreover, LP-BER reduced plasma triglycerides levels.

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Pharmacokinetic of meglumine antimoniate encapsulated in phosphatidylserine-liposomes in mice model: A candidate formulation for visceral leishmaniasis

Cited by 15 publications

References 40 publications

Targeting intracellular Leishmania (L.) infantum with nitazoxanide entrapped into phosphatidylserine-nanoliposomes: An experimental study

Targeting intracellular Leishmania (L.) infantum with nitazoxanide entrapped into phosphatidylserine-nanoliposomes: An experimental study

Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

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