scholarly journals In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil

2021 ◽  
Vol 9 (6) ◽  
pp. 1228
Author(s):  
Caroline Ricce Espada ◽  
Erica V. de Castro Levatti ◽  
Mariana Côrtes Boité ◽  
Dorcas Lamounier ◽  
Jorge Alvar ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Oral Drug ◽  
Efficacy And Safety ◽  
In Vitro Susceptibility ◽  
Intracellular Amastigotes ◽  
Geographic Regions ◽  
Therapeutic Tools ◽  
Cure Rates ◽  
Intracellular Amastigote

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC50 for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 μM. The EC50 of the 73 strains determined in promastigotes varied between 5.89 and 23.7 μM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil.

scholarly journals Leishmanicidal Activity of Nine Novel Flavonoids fromDelphinium staphisagria

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Inmaculada Ramírez-Macías ◽  
Clotilde Marín ◽  
Jesús G. Díaz ◽  
María José Rosales ◽  
Ramón Gutiérrez-Sánchez ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Mammalian Cells ◽  
Mechanisms Of Action ◽  
Reference Drug ◽  
Ultrastructural Alteration ◽  
Leishmanicidal Activity ◽  
Design And Methods ◽  
Electronic Microscope ◽  
Intracellular Amastigote

Objectives. To evaluate thein vitroleishmanicidal activity of nine flavonoid derivatives fromDelphinium staphisagriaagainstL. infantumandL. braziliensis.Design and Methods. Thein vitroactivity of compounds1–9was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies.Results. Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms ofLeishmania infantumandL. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that2″-acetylpetiolaroside (compound8) was clearly the most active.Conclusion. This study has demonstrated that flavonoid derivatives are active againstL. infantumandL. braziliensis.

scholarly journals Intracellular amastigote replication may not be required for successful in vitro selection of miltefosine resistance in Leishmania infantum

2015 ◽  
Vol 114 (7) ◽  
pp. 2561-2565 ◽  
Author(s):  
S. Hendrickx ◽  
A. Mondelaers ◽  
E. Eberhardt ◽  
L. Lachaud ◽  
P. Delputte ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
In Vitro Selection ◽  
Intracellular Amastigote ◽  
Selection Of

scholarly journals An axenic amastigote system for drug screening.

1997 ◽  
Vol 41 (4) ◽  
pp. 818-822 ◽  
Author(s):  
H L Callahan ◽  
A C Portal ◽  
R Devereaux ◽  
M Grogl
Keyword(s):  
Drug Screening ◽  
Inhibitory Concentration ◽  
Rapid Testing ◽  
Intracellular Amastigotes ◽  
Axenic Amastigotes ◽  
Parasite Stage ◽  
Intracellular Amastigote ◽  
Selection Of

Currently available primary screens for selection of candidate antileishmanial compounds are not ideal. The choices include screens that are designed to closely reflect the situation in vivo but are labor-intensive and expensive (intracellular amastigotes and animal models) and screens that are designed to facilitate rapid testing of a large number of drugs but do not use the clinically relevant parasite stage (promastigote model). The advent of successful in vitro culture of axenic amastigotes permits the development of a primary screen which is quick and easy like the promastigote screen but still representative of the situation in vivo, since it uses the relevant parasite stage. We have established an axenic amastigote drug screening system using a Leishmania mexicana strain (strain M379). A comparison of the 50% inhibitory concentration (IC50) drug sensitivity profiles of M379 promastigotes, intracellular amastigotes, and axenic amastigotes for six clinically relevant antileishmanial drugs (sodium stibogluconate, meglumine antimoniate, pentamidine, paromomycin, amphotericin B, WR6026) showed that M379 axenic amastigotes are a good model for a primary drug screen. Promastigote and intracellular amastigote IC50s differed for four of the six drugs tested by threefold or more; axenic amastigote and intracellular amastigote IC50s differed by twofold for only one drug. This shows that the axenic amastigote susceptibility to clinically used reference drugs is comparable to the susceptibility of amastigotes in macrophages. These data also suggest that for the compounds tested, susceptibility is intrinsic to the parasite stage. This contradicts previous hypotheses that suggested that the activities of antimonial agents against intracellular amastigotes were solely a function of the macrophage.

scholarly journals In vitro effects of purine and pyrimidine analogues on Leishmania donovani and Leishmania infantum promastigotes and intracellular amastigotes

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Samira Azzouz ◽  
Philippe Lawton
Keyword(s):  
Metabolic Pathways ◽  
Leishmania Infantum ◽  
Leishmania Donovani ◽  
Purine Salvage ◽  
Intracellular Amastigotes ◽  
Pyrimidine Analogues ◽  
In Vitro Effects ◽  
Salvage Pathways ◽  
Purine Salvage Pathways

AbstractInhibition of parasite metabolic pathways is a rationale for new chemotherapeutic strategies. The pyrimidine and purine salvage pathways are thus targets against

scholarly journals In Vitro Activities of Position 2 Substitution-Bearing 6-Nitro- and 6-Amino-Benzothiazoles and Their Corresponding Anthranilic Acid Derivatives against Leishmania infantum and Trichomonas vaginalis

2002 ◽  
Vol 46 (8) ◽  
pp. 2588-2594 ◽  
Author(s):  
Florence Delmas ◽  
Carole Di Giorgio ◽  
Maxime Robin ◽  
Nadine Azas ◽  
Monique Gasquet ◽  
...  
Keyword(s):  
Benzoic Acid ◽  
Anthranilic Acid ◽  
Leishmania Infantum ◽  
Trichomonas Vaginalis ◽  
No Production ◽  
Protective Mechanisms ◽  
Anthranilic Acid Derivatives ◽  
Intracellular Amastigote ◽  
Amino Benzoic Acid

ABSTRACT 6-Nitro- and 6-amino-benzothiazoles bearing different chains in position 2 and their corresponding anthranilic acid derivatives were investigated for their in vitro antiparasitic properties against parasites of the species Leishmania infantum and Trichomonas vaginalis compared to their toxicity towards human monocytes. Biological investigations established that the antiprotozoal properties depended greatly on the chemical structure of the position 2 substitution-bearing group. Compound C1, 2-[(2-chloro-benzothiazol-6-yl) amino] benzoic acid, demonstrated an interesting antiproliferative activity towards parasites of the species T. vaginalis, while compound C11, 2-({2-[(2-hydroxyethyl) amino]-benzothiazol-6-yl} amino) benzoic acid, exhibited a promising activity against parasites of the species L. infantum in their intracellular amastigote form. Additional experiments established that compound C11, which was poorly toxic against the promastigote and the extracellular amastigote forms of the parasite, could improve host-protective mechanisms against Leishmania by preventing parasite internalization by macrophages and stimulating NO production, by means of a mechanism synergistically enhanced by the presence of gamma interferon.

scholarly journals Reversible Cysteine Protease Inhibitors Show Promise for a Chagas Disease Cure

2013 ◽  
Vol 58 (2) ◽  
pp. 1167-1178 ◽  
Author(s):  
Momar Ndao ◽  
Christian Beaulieu ◽  
W. Cameron Black ◽  
Elise Isabel ◽  
Fabio Vasquez-Camargo ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Cysteine Protease ◽  
Chemotherapeutic Agents ◽  
Enzyme Assays ◽  
Cysteine Protease Inhibitors ◽  
Content Type ◽  
Control Compound ◽  
Cure Rates ◽  
Intracellular Amastigote

ABSTRACTThe cysteine protease cruzipain is essential for the viability, infectivity, and virulence ofTrypanosoma cruzi, the causative agent of Chagas disease. Thus, inhibitors of cruzipain are considered promising anti-T. cruzichemotherapeutic agents. Reversible cruzipain inhibitors containing a nitrile “warhead” were prepared and demonstrated 50% inhibitory concentrations (IC50s) as potent as 1 nM in baculovirus-generated cruzipain enzyme assays. In epimastigote and intracellular amastigotein vitroassays, the most potent compounds demonstrated antiparasitic behavior in the 5 to 10 μM IC50range; however, trypomastigote production from the amastigote form was ∼90 to 95% inhibited at 2 μM. Two key compounds, Cz007 and Cz008, with IC50s of 1.1 and 1.8 nM, respectively, against the recombinant enzyme were tested in a murine model of acuteT. cruziinfection, with oral dosing in chow for 28 days at doses from 3 to 50 mg/kg of body weight. At 3 mg/kg of Cz007 and 3 mg/kg of Cz008, the blood parasitemia areas under the concentration-time curves were 16% and 25% of the untreated group, respectively. At sacrifice, 24 days after immunosuppression with cyclophosphamide, parasite presence in blood, heart, and esophagus was evaluated. Based on negative quantitative PCR results in all three tissues, cure rates in surviving animals were 90% for Cz007 at 3 mg/kg, 78% for Cz008 at 3 mg/kg, and 71% for benznidazole, the control compound, at 50 mg/kg.

scholarly journals Treatment of canine visceral leishmaniasis with Milteforan™ induces Leishmania infantum resistance to miltefosine and amphotericin B

2021 ◽  
Author(s):  
Gustavo Gonçalves ◽  
Monique Paiva Campos ◽  
Alessandra Silva Gonçalves ◽  
Lia Carolina Soares Medeiros ◽  
Fabiano Borges Figueiredo
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Infantum ◽  
Cross Resistance ◽  
Canine Visceral Leishmaniasis ◽  
In Vitro Susceptibility ◽  
Meglumine Antimoniate ◽  
Parasite Fitness ◽  
The Impact

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is caused by Leishmania infantum in the Americas. Since the use of Milteforam™ was authorized to treat canine visceral leishmaniasis (CVL) in Brazil in 2017, there has also been fear of the emergence of parasites resistant to this drug and, through cross-resistance mechanisms, to meglumine antimoniate and amphotericin B. Additionally, the literature shows that acquisition of resistance is followed by increased parasite fitness, with higher rates of proliferation, infectivity and metacyclogenesis, which are determining factors for parasite virulence. In this context, this study aims to analyze the impact of treating a dog with Milteforan™ on the generation of parasites resistant to miltefosine, meglumine antimoniate, and amphotericin B. To this end, in vitro susceptibility tests were conducted against these drugs with T0 (parasites isolated from the dog before treatment with Milteforan™), T1 (after one course of treatment), and T2 (after two courses of treatment) isolates. The rates of cell proliferation, infectivity, and metacyclogenesis of the isolates were also evaluated. The results indicate a gradual increase in parasite resistance to miltefosine and amphotericin B with increasing the number of treatment courses. A trend increase in the metacyclogenesis rate of the parasites was also observed as drug resistance increased. Therefore, treatment of CVL with Milteforan™ induces resistance to miltefosine and amphotericin B as well as changes in parasite fitness, and may have an impact on animal and human public health.

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