RESUMO

Leishmaniasis is an infectious disease responsible for a huge rate of morbidity and mortality in humans. Chemotherapy consists of the use of pentavalent antimonial, amphotericin B, pentamidine, miltefosine, and paromomycin. However, these drugs are associated with some drawbacks such as high toxicity, administration by parenteral route, and most seriously the resistance of some strains of the parasite to them. Several strategies have been used to increase the therapeutic index and reduce the toxic effects of these drugs. Among them, the use of nanosystems that have great potential as a site-specific drug delivery system stands out. This review aims to compile results from studies that were carried out using first- and second-line antileishmanial drug-carrying nanosystems. The articles referred to here were published between 2011 and 2021. This study shows the promise of effective applicability of drug-carrying nanosystems in the field of antileishmanial therapeutics, with the perspective of providing better patient adherence to treatment, increased therapeutic efficacy, reduced toxicity of conventional drugs, as well as the potential to efficiently improve the treatment of leishmaniasis.

Assuntos

RESUMO

Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 µg/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 µg STL/2× day/60 d, 72.7% at doses of 19.2 µg STL/1× d/60 d and 67% at a dose of 38.4 µg STL/2× d/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 µg STL/2× day/60 d and 71% at a dose of 38.4 µg STL/2× d/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL.

RESUMO

Leishmaniasis are endemic diseases caused by different species of intracellular parasites of the genus Leishmania. Due to the high toxicity and drug resistance of current antileishmanial drugs, it is necessary to identify new and more effective drugs. Previously, we investigated the immunomodulatory and anti-Trypanosoma cruzi action of BA5, a derivative of betulinic acid. In the present study, we investigated the in vitro activity of BA5 against different species of Leishmania and their action mechanism. BA5 exhibited low cytotoxicity against macrophages and inhibited the proliferation of promastigote forms of Leishmania amazonensis (IC50 = 4.5 ± 1.1 µM), Leishmania major (IC50 = 3.0 ± 0.8 µM), Leishmania braziliensis (IC50 = 0.9 ± 1.1 µM) and Leishmania infantum (IC50 = 0.15 ± 0.05 µM). Incubation with BA5 reduced the percentage of Leishmania amazonensis-infected macrophages and the number of intracellular parasites (IC50 = 4.1 ± 0.7 µM). To understand the mechanism of action underlying BA5 antileishmanial activity (incubation at IC50/2, IC50 or 2xIC50 values of the drug), we investigated ultrastructural changes by scanning electron microscopy and evaluated cell cycle, membrane mitochondrial potential, and cell death against promastigote forms of Leishmania amazonensis by flow cytometry. Promastigotes incubated with BA5 presented membrane blebbing, flagella damage, increased size, and body deformation. Flow cytometry analysis showed that parasite death is mainly caused by apoptosis-like death, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of Leishmania amazonensis. Surprisingly, the combination of BA5 and amphotericin B, an assay used to determine the degree of drug interaction, revealed synergistic effects (CI = 0.15 ± 0.09) on promastigotes forms of Leishmania amazonensis. In conclusion, BA5 compound is an effective and selective antileishmanial agent.

RESUMO

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.

Assuntos

RESUMO

The activation of proinflammatory cellular processes and signals such as those linked to NF-kB in macrophages are involved in the control of infection by Leishmania ssp. However, little is known about the influence of the drugs used in the treatment on the host cellular inflammatory signaling pathways. This study aimed to evaluate the effects of different drugs used in the treatment of leishmaniasis on inflammatory profile related to Toll-like receptors (TLRs) from L. amazonensis-infected macrophages. J774 macrophage-like cells were infected with the promastigote forms (5:1) and 24 hs incubated with Amphotericin B (AmB), Glucantime® (GLU) or Pentamidine (Pent). The following inflammatory pathways were evaluated: NF-κB p65, NF-κB p65 phosphorylated (Ser536), stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) phosphorylated (Thr183/Tyr185), p38 mitogen activated protein kinase (MAPK p38) phosphorylated (Thr180/Tyr182), signal transducer and activator of transcription-3 (Stat3) phosphorylated (Tyr705) and inhibitor kappa B-α (IκB-α) phosphorylated (Ser32). In silico tests were performed to evaluate the molecular affinity between TLRs and antileishmanial drugs. Molecular docking showed that affinities varied significantly among the binders evaluated. The lowest affinity (-8.6 Kcal/Mol) was calculated for AmB in complex with TLR4. Pent showed higher values for TLR1, TLR2 and TLR3, while for TLR4 the affinity value was lower (5.5 Kcal/Mol). The values obtained for GLU were the highest for the set of binders tested. From the infected macrophages, treatments inhibited NF-kB p65 for GLU (65.44%), for Pent (46.43%) and for AmB (54.07%) compared to untreated infected macrophages. The activation of the signaling pathway of NF-kB, SAPK/JNK and IκB-α caused by AmB and Pent may potentiate the microbicidal mechanisms of the infected macrophages.

Assuntos

RESUMO

AIM: The purpose of this study was to evaluate the effects of the antileishmanials meglumine antimoniate and pentamidine against Sporothrix schenckii complex. MATERIALS & METHODS: The antifungal activity of the two antileishmanials was assessed by broth microdilution. The interaction between the antileishmanials and antifungal drugs (amphotericin B, itraconazole and terbinafine) was evaluated by the checkerboard assay. The effect of prior exposure of Sporothrix spp. yeast cells to antileishmanials was evaluated by broth microdilution. RESULTS: Only pentamidine showed antifungal activity against Sporothrix spp. Synergistic interactions were observed between pentamidine and the antifungals. Also, the pre-exposure to meglumine antimoniate reduced the susceptibility of Sardinella brasiliensis and S. schenckii sensu stricto to amphotericin B and itraconazole. CONCLUSION: Pentamidine showed antifungal activity against Sporothrix spp., indicating it is a possible therapeutic alternative for the treatment of sporotrichosis.

Assuntos

RESUMO

Most of the procedures for antimony determination require time-consuming sample preparation (e.g. liquid-liquid extraction with organic solvents), which are harmful to the environment. Because of the high antimony toxicity, a rapid, sensitive and greener procedure for its determination becomes necessary. The goal of this work was to develop an analytical procedure exploiting for the first time the cloud point extraction on a lab-in-syringe flow system aiming at the spectrophotometric determination of antimony. The procedure was based on formation of an ion-pair between the antimony-iodide complex and H(+) followed by extraction with Triton X-114. The factorial design showed that the concentrations of ascorbic acid, H2SO4 and Triton X-114, as well as second and third order interactions were significant at the 95% confidence level. A Box-Behnken design was applied to obtain the response surfaces and to identify the critical values. System is robust at the 95% confidence level. A linear response was observed from 5 to 50 µg L(-1), described by the equation A=0.137+0.050C(Sb) (r=0.998). The detection limit (99.7% confidence level), the coefficient of variation (n=5; 15 µg L(-1)) and the sampling rate was estimated at 1.8 µg L(-1), 1.6% and 16 h(-1), respectively. The procedure allows quantification of antimony in the concentrations established by environmental legislation (6 µg L(-1)) and it was successfully applied to the determination of antimony in freshwater samples and antileishmanial drugs, yielding results in agreement with those obtained by HGFAAS at the 95% confidence level.

RESUMO

New synthetic compounds based on tetrahydroindenoquinoline structure were evaluated for their in vitro antileishmanial activities. The seven compounds assayed have antiproliferative activities against promastigotes of Leishmania mexicana. Compound 1 and 3 were the most active (IC50 1.0 µg/ml) and showed high selectivity towards the parasite. These compounds were selected to evaluate their effect on promastigote morphology and mitochondrial transmembrane potential as well as on the amastigote capability to survive into macrophages J774 cell line. Whereas compound 1 affected the promastigote cell cycle, compound 3 induced morphological changes and the total collapse of the mitochondrial transmembrane potential, a hallmark of apoptosis. Both compounds also affected the amastigote form of the parasite, decreasing their survival rate in J774 macrophages. Due to the greatest selectivity index, the apparent effect as apoptotic inducer and its sustained inhibition on intracellular amastigote replication, compound 3 is the best candidate to be tested in vivo. This compound is worth considering for the development of new antileishmanial drugs.

Assuntos