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1.
Ann Parasitol ; 62(2): 157-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32531148

RESUMO

Leishmaniosis is one of the most serious public health concern with a worldwide distribution. Since the current treatments of leishmaniosis are toxic and expensive, frequent studies have been conducted to investigate the benefits of new resources such as medicinal plants for treatment of this infectious disease. Recent studies revealed the antiparasitic potential of Rhus coriaria. Here we investigated the potential antileishmanial and antibacterial activities of the hydroalcoholic extract of R. coriaria fruits. The fruits were extracted using 80% methanol by maceration method. The concentrations of 312, 156, 78, and 37 µg/ml of the extract were added separately to the wells containing Leishmania major (L. major) promastigotes and amastigotes. Amphotericin B was considered as positive control. Finally, the death rate was determined for the extract-treated parasites as compared to the non-treated parasite. The antibacterial activity was evaluated by measurement of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extract against a set of Gram-positive and Gram-negative bacteria. The extract significantly inhibited the growth of both promastigotes (60,7%) and amastigotes (59%) at the concentration of 312 µg/ml with the IC50 values of 147 µg/ml and 233 µg/ml, respectively. The extract showed bactericidal effects against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Acinetobacter baumannii. Totally, Grampositive bacteria were more susceptible to the extract. Our findings show that the hydroalcoholic extract of R. coriaria fruits are rich in tannins and can be considered for further in vivo studies on the antileishmanial and antibacterial activities especially on dermal lesions caused by L. major.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Extratos Vegetais/farmacologia , Rhus/química , Frutas/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leishmania major/efeitos dos fármacos
2.
Exp Parasitol ; 213: 107902, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32353376

RESUMO

Natural compounds played an important role for prevention and treatment of the disease as well as are the important compounds for the design of the new bioactive compounds. In this study, eight tropolone alkaloids were isolated from Colchicum kurdicum including colchicoside, 2-demethyl colchicine, 3-demethyl colchicine, demecolcine, colchifoline, N-deacetyl-N-formyl colchicine, colchicine and cornigerine by column and preparative thin layer chromatography. The chemical structures were identified by 1H NMR and 13C NMR spectroscopy. Moreover, the antileishmanial activity on Leishmania major, anti-inflammatory activity, iron chelating activity and toxicity studies including hemolytic activity, brine shrimp toxicity, cytotoxicity and acute toxicity and docking study of all isolated bioactive compounds were evaluated. As result, colchicoside and colchicine had potent leishmanicidal effects and N-deacetyl-N-formyl colchicine and cornigerine had the highest anti-inflammatory effects. All compounds had the significant iron chelating activity. According to toxicity studies, isolated compounds showed the low hemolytic activity and cytotoxicity, high LC50, LC90 and LD50. In the molecular docking study, colchicoside had the high dockscore. According to the study, with future studies all isolated compounds could be used for design the novel antileishmanial drugs.


Assuntos
Alcaloides/farmacologia , Colchicum/química , Leishmania major/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tripanossomicidas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Tropolona/química , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação
3.
J Nat Med ; 74(3): 606-611, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277328

RESUMO

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1-4 displayed anti-leishmanial activity. The 50% growth inhibition (GI50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 µM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 µM and GI50 values between 2.5 and 2.9 µM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI50 values of 100 µM and 31.5-46.2 µM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI50 value of 1.5 µM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis.


Assuntos
Leishmania major/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Limoninas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Animais , Células HL-60 , Humanos , Testes de Sensibilidade Microbiana
4.
Biochim Biophys Acta Gen Subj ; 1864(6): 129558, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061714

RESUMO

BACKGROUND: Cutaneous leishmaniasis is a parasitic disease, which is difficult to treat due to high drug resistance and adverse side effects. Photodynamic therapy by ultraviolet radiation using materials with high photocatalytic features like titanium dioxide nanoparticles (TiO2-NPs) is an emerging treatment for this disease. In this study, TiO2-NPs with ultraviolet (UV) radiation were administered as photodynamic therapy against Leishmania Major (LM) promastigotes. METHODS: Two forms of TiO2 viz. including Anatase and Rutile were administered in two UV ranges< UVA and UVB for different time periods (30 and 60 min). Finally, 24 and 48 h after incubation, the MTS test was performed and cell survival percentage was calculated. RESULTS: The mean size of Anatase and Rutile-NPs is approximately 32.5 and 50.9 nm respectively by DLS and FE-SEM, and crystal phase is emphasized by XRD. The combined treatment of LM with TiO2-NPs and UV has significant effects on LM promastigotes, which vary depending on NP and UV types. The synergistic effect was anticipated in the groups irradiated by UV-B in the presence of Rutile NPs. CONCLUSION: The combined treatment with UV- radiation and TiO2-NPs can be effective in killing the promastigotes of Leishmania major. The proper concentration of NPs and the type of UV-radiation must be taken into consideration. The results suggest improved treatment methods, after proper in vivo studies.


Assuntos
Leishmaniose Cutânea/terapia , Nanopartículas Metálicas/química , Titânio/farmacologia , Terapia Ultravioleta , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Leishmania major/efeitos dos fármacos , Leishmania major/patogenicidade , Leishmania major/efeitos da radiação , Leishmaniose Cutânea/parasitologia , Nanopartículas Metálicas/administração & dosagem , Microscopia Eletrônica de Transmissão , Fotoquimioterapia/métodos , Titânio/química
5.
PLoS Negl Trop Dis ; 14(1): e0007843, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929528

RESUMO

BACKGROUND: Neglected parasitic diseases (NTDs) like cutaneous leishmaniasis (CL) have caused high mortality and morbidity rate in developing countries. This disease is considered as one of the six major tropical diseases, and has a great importance in HIV infected individuals as an opportunistic infection in those areas that both infections are endemic. This study evaluated the therapeutic effects of the Urtica dioica L (U. dioica) aqueous extract as an anti-leishmanial herbal drug in-vitro and in-vivo, and in addition to that, evaluated two vital immune system cytokines including gamma interferon (IFN-γ) and interleukin-4 (IL-4) plus nitric oxide (NO) and arginase activity against Leishmania major (L. major) infected mice. METHODOLOGY/PRINCIPAL FINDINGS: In-vitro anti-leishmanial activity of U. dioica aqueous extract was determined using MTT method and also Parasite Rescue Transformation Assay. Also, the footpad lesion size and parasite load in BALB/c mice infected with L. major were quantified for in-vivo assessment. Furthermore, for evaluating the immune responses, the levels of IFN-γ, IL-4, NO and arginase were measured in the BALB/c mice. These results indicated that U. dioica extract significantly reduced the L. major promastigotes viability. According to the in-vitro cytotoxicity assay of the extract on Leishmania parasites (CC50) and infected macrophages (EC50), the extract had no toxicity to the macrophages, however it efficiently killed the L. major amastigotes. In addition, the lesion size, parasite load, IL-4, and ARG were decreased in the treated infected mice, however IFN-γ and NO were significantly increased. CONCLUSIONS/SIGNIFICANCE: This study established satisfactory results in Leishmania parasite clearing both in-vivo and in-vitro. Therefore, U. dioica extract can be considered as an effective and harmless herbal compound for killing the parasite without toxicity to the host macrophages. Furthermore, it also can treat the CL by switching the mouse immune response towards a cell-mediated response (Th1); hence, it may be identified as a perfect therapeutic herbal drug for CL treatment.


Assuntos
Leishmania major/efeitos dos fármacos , Extratos Vegetais/farmacologia , Urtica dioica/química , Animais , Antiprotozoários/farmacologia , Arginase/metabolismo , Linhagem Celular , Interferon gama/metabolismo , Interleucina-4/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Carga Parasitária , Extratos Vegetais/toxicidade , Urtica dioica/toxicidade
6.
Sci Rep ; 10(1): 785, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964958

RESUMO

Present work aims to utilize systems biology and molecular modelling approach to understand the inhibition kinetics of Leishmania major GLO I and identifying potential hit followed by their validation through in vitro and animal studies. Simulation of GLO I inhibition has shown to affect reaction fluxes of almost all reactions in the model that led to increased production of various AGEs and free radicals. Further, in vitro testing of C1 and C2, selected through molecular modelling revealed remarkable morphological alterations like size reduction, membrane blebbing and loss in motility of the parasite, however, only C1 showed better antileishmanial activity. Additionally, C1 showed apoptosis mediated leishmanicidal activity (apoptosis-like cell death) along with cell-cycle arrest at sub-G0/G1 phase and exhibited potent anti-leishmanial effect against intracellular amastigotes. Furthermore, decrease in parasite load was also observed in C1 treated BALB/c female mice. Our results indicate that C1 has healing effect in infected mice and effectively reduced the parasitic burden. Hence, we suggest C1 as a lead molecule which on further modification, may be used to develop novel therapeutics against Leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Lactoilglutationa Liase/química , Lactoilglutationa Liase/metabolismo , Leishmania major/crescimento & desenvolvimento , Animais , Antiprotozoários/química , Ciclo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Lactoilglutationa Liase/antagonistas & inibidores , Leishmania major/efeitos dos fármacos , Leishmania major/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Carga Parasitária , Células RAW 264.7 , Biologia de Sistemas
7.
Int J Pharm ; 578: 119057, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31991188

RESUMO

Miltefosine (MF), an alkylphospholipid originally developed for breast cancer treatment, is a highly active drug for the treatment against leishmaniasis, a neglected tropical disease considered the world's second leading cause of death by a parasitic agent after malaria. MF exhibits dose-limiting gastrointestinal side effects in patients and its penetration through lipophilic barriers is reduced. In this work we propose a reformulation of MF by incorporating the drug to poly(ethylene)oxide (PEO)-based polymeric micelles, specifically, D-α-tocopheryl polyethylene glycol succinate (TPGS) and Tetronic block copolymers (T904 and T1107). A full structural characterization of the aggregates has been carried out by SANS (small-angle neutron scattering) and dynamic light scattering (DLS), in combination with proton 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, to determine the precise location of the drug. The structure of MF micelles has been characterized as a function of the temperature and concentration. In the presence of the block-copolymers, MF forms mixed micelles in a wide range of temperatures, TPGS being the co-surfactant that incorporates more MF unimers. The hydrophobic tail of MF and those of the block copolymers are in close contact within the micelles, which present a core-shell structure with a hydrophilic corona formed by the PEG blocks of the TPGS and the zwitterion head group of the MF. In order to identify the best carrier, the antileishmanicidal activity of MF in the different formulations has been tested on macrophages, promastigotes and intracellular amastigotes. The combination of the three vehicles with MF makes the formulated drug more active than MF alone against L. major promastigotes, however, only the combination with T904 increases the MF activity against intracellular amastigotes. With the aim of exploring gel-based formulations of the drug, the combination of MF and T1107 under gelation conditions has also been investigated.


Assuntos
Antiprotozoários/administração & dosagem , Portadores de Fármacos/administração & dosagem , Etilenodiaminas/administração & dosagem , Leishmania major/efeitos dos fármacos , Micelas , Fosforilcolina/análogos & derivados , Vitamina E/administração & dosagem , Animais , Antiprotozoários/química , Portadores de Fármacos/química , Difusão Dinâmica da Luz , Etilenodiaminas/química , Macrófagos/parasitologia , Camundongos , Estrutura Molecular , Nanopartículas/administração & dosagem , Nanopartículas/química , Fosforilcolina/administração & dosagem , Fosforilcolina/química , Análise Espectral , Vitamina E/química
8.
Eur J Med Chem ; 186: 111895, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771825

RESUMO

A series of eight alkyl gallium complexes of general formulae [GaMe2(L)] and [Ga(Me)2L] have been synthesised, characterised and their antimicrobial activity against bacteria, cancer cells and Leishmania assessed. All eight complexes are novel, with the solid-state structures of all complexes successfully authenticated by single crystal X-ray diffraction. The dimethyl complexes all adopt a four-coordinate tetrahedral confirmation, while the monomethyl complexes are five-coordinate trigonal bipyramidal. All complexes were screened for their anti-bacterial activity either by solution state diffusion, or a solid-state stab test. The five soluble complexes underwent testing against two differing mammalian cell controls, with excellent selectivity observed against COS-7 cells, with an IC50 range of 88.5 µM to ≥100 µM. Each soluble complex was also tested for their anti-cancer capabilities, with no significant activity observed. Excellent activity was exhibited against the protozoan parasite Leishmania major (strain: V121) in both the promastigote and amastigote forms, with IC50 values ranging from 1.11 µM-13.4 µM for their anti-promastigote activity and % infection values of 3.5% ± 0.65-11.5% ± 0.65 for the more clinically relevant amastigote. Selectivity indices for each were found to be in the ranges of 6.61-64.7, with significant selectivity noted for two of the complexes. At minimum, the gallium complexes show a 3-fold enhancement in activity towards the Leishmaniaamastigotes over the parent quinolinols alone.


Assuntos
Antiprotozoários/farmacologia , Complexos de Coordenação/farmacologia , Gálio/farmacologia , Hidroxiquinolinas/farmacologia , Leishmania major/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Células COS , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Gálio/química , Células HeLa , Humanos , Hidroxiquinolinas/química , Leishmania major/metabolismo , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/análise , Relação Estrutura-Atividade
9.
Exp Parasitol ; 209: 107823, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31862270

RESUMO

Typically, antimicrobial peptides (AMPs) are short positive charged peptides serving a key role in innate immunity as well as antimicrobial activity. Discovering novel therapeutic agents is considered as an undeniable demand due to increasing microbial species with antibiotic resistance. In this direction, the unique ability of AMPs to modulate immune responses highlighted them as novel drug candidates in the field of microbiology. Patients affected by leishmaniasis; a neglected tropical disease, confront serious problems for their treatment including resistance to common drugs as well as toxicity and high cost of therapy. So, there is a need for development of new drug candidates to control the diseases. Jellein, a peptide derived from royal jelly of honeybee has been shown to have promising effect against several bacterial and fungal species. In current study, anti-leishmanial effect of Jellein and its lauric acid conjugated form was investigated against two forms of Leishmania major (L. major) parasite. Moreover, cytotoxic effect of these peptides was studied in THP1 cell line and human Red Blood Cells (RBCs). Furthermore, the mechanism of action of peptides on L. major promastigotes was assessed through different methods. The results demonstrated that, conjugation of lauric acid to Jellein not only had no effect on the elevation of antimicrobial activity but also halted it completely. Moreover, Jellein caused a limitation in the number of L. major promastigotes by pore formation as well as changing the membrane potential rather than induction of apoptosis or activation of caspases.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Oligopeptídeos/química , Antígenos de Diferenciação de Linfócitos B/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/toxicidade , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Caspases/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Ácidos Graxos/química , Citometria de Fluxo , Hemólise , Antígenos de Histocompatibilidade Classe II/farmacologia , Humanos , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Ácidos Láuricos/toxicidade , Leishmania major/ultraestrutura , Potenciais da Membrana/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Oligopeptídeos/toxicidade
10.
Chem Biodivers ; 17(2): e1900597, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31804031

RESUMO

A series of bis-naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a, 3,4-difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5-trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.


Assuntos
Antiparasitários/química , Naftoquinonas/química , Antiparasitários/síntese química , Antiparasitários/farmacologia , Humanos , Leishmania major/efeitos dos fármacos , Leishmania major/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Relação Estrutura-Atividade , Toxoplasma/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos
11.
Int J Nanomedicine ; 14: 7593-7607, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802863

RESUMO

Background: Amphotericin B (Amp) and Betulinic acid (BA) as antileishmanial agents have negligible water solubility and high toxicity. To solve these problems, for the first time, chitosan nanoparticles and Anionic Linear Globular Dendrimer (D) were synthesized for the treatment of Leishmania major (L. major). Method: Chitosan and dendrimer nanoparticles were synthesized, and Amp and BA were loaded into the nanoparticles. The particles were then characterized using various methods and their efficacy was evaluated in vitro and in vivo environments (parasite burden was confirmed using pathological studies and real-time PCR methods). Result: The results of docking showed that Amp and BA can be loaded into chitosan and dendrimer nanoparticles. The results of physically drug loading efficiency for AK (Amphotericin B-chitosan), BK (Betulinic acid-chitosan), AD (Amphotericin B-Dendrimer) and BD (Betulinic acid- Dendrimer) were 90, 93, 84 and 96 percent, respectively. The characterization results indicated that the drugs were loaded into nanoparticles physically. Moreover, the increased solubility rate for AD=478, BD=790, AK=80 and BK=300 folds. Furthermore, the results of the drug delivery system showed the slow controlled drug release pattern with cellular uptake of more than 90%. The treatment results showed a 100 percent decrease of toxicity for the all nanodrugs was observed in vivo and in vitro environments. Moreover, AK10 and BK20 mg/kg reduced parasite burden by 83 percent (P<0.001), while AD50 and BD40 mg/kg reduced it to a lesser extent compared to glucantime. Conclusion: All the synthesized nanodrugs were completely succeeded by 100% to recovery the L. major induced pathological effects in the infected footpad. Also, the results of present study were confirmed with real-time PCR and the results showed that AK and BK were succeeded in a large extent to the treatment of L. major infection (P<0.001), therefore AK and BK could be considered as proper alternatives of choices drugs.


Assuntos
Anfotericina B/farmacologia , Quitosana/química , Dendrímeros/química , Leishmania major/efeitos dos fármacos , Leishmania major/genética , Nanopartículas/química , Reação em Cadeia da Polimerase em Tempo Real/métodos , Triterpenos/química , Anfotericina B/química , Animais , Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Simulação de Acoplamento Molecular , Nanopartículas/uso terapêutico , Nanopartículas/toxicidade , Parasitos/efeitos dos fármacos , Parasitos/genética , Triterpenos Pentacíclicos , Solubilidade , Termodinâmica
12.
Biomolecules ; 9(11)2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718000

RESUMO

The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.


Assuntos
Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Paromomicina/efeitos adversos , Proteínas Serina-Treonina Quinases/genética , Antiprotozoários , Resistência a Medicamentos/genética , Humanos , Leishmania major/enzimologia , Leishmania major/patogenicidade , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/parasitologia , Simulação de Dinâmica Molecular , Paromomicina/química , Proteínas Serina-Treonina Quinases/química
13.
Int J Parasitol Drugs Drug Resist ; 11: 156-165, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31582344

RESUMO

BACKGROUND: Currently, there is no topical treatment available for any form of cutaneous leishmaniasis (CL) in most of the endemic areas. The aim of the current study was to develop a topical nano-liposomal Amphotericin B (AmB) for the treatment of CL. METHODOLOGY/PRINCIPAL FINDINGS: Liposomes containing 0.1, 0.2 and 0.4% AmB (Lip-AmB) were formulated and characterized for the size, entrapment efficiency, long term stability, and skin penetration properties using Franz diffusion cells. Liposomes diameters were around 100 nm with no change during more than 20 months' storage either at 4 °C or at room temperature. Franz diffusion cells studies showed that almost 4% of the applied formulations penetrated across the skin and the highest skin retention (73.92%) observed with Lip-AmB 0.4%. The median effective doses (ED50), the doses of AmB required to kill 50% of L. major amastigotes were 0.151, 0.151, and 0.0856 (µg/mL) in Lip-AmB 0.1, 0.2, 0.4%, respectively. Lip-AmB 0.4% caused 80% reduction in fluorescence intensity of GFP+ L. tropica infected macrophages at 5 µg/mL of AmB concentration. Topical Lip-AmB was applied twice a day for 4 weeks to the skin of BALB/c mice to treat lesions caused by L. major. Results showed the superiority of Lip-AmB 0.4% compared to Lip-AmB 0.2 and 0.1%. The parasite was completely cleared from the skin site of infection and spleens at week 8 and 12 post-infection in mice treated with Lip-AmB 0.4%. The results suggest that topical Lip-AmB 0.4% may be a useful tool in the treatment of CL and merits further investigation.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Administração Cutânea , Animais , Feminino , Leishmania major/efeitos dos fármacos , Leishmania major/crescimento & desenvolvimento , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Pele/parasitologia , Pele/patologia
14.
Acta Trop ; 200: 105173, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525323

RESUMO

Leishmanization (LZ) is an intradermal inoculation of live Leishmania to induce an artificial cutaneous leishmaniasis (CL) lesion in a covered part of the body to protect against further natural CL lesion development. Leishmanization has been used from ancient times and when NNN medium was developed continued with using Leishmania from culture media. The objective of this study was to review LZ published experiences. This article is a review of LZ experiences and historical studies initiated since 1910 when Leishmania promastigotes were harvested from culture media and used for LZ. This review includes LZ experiences in Israel, some countries of Former Soviet Union and Iran. The results of LZ in Israel, some countries of Former Soviet Union and Iran showed that despite limitations, using this method significantly reduced the incidence rate of CL among leishmanized individuals in endemic areas. In conclusion, leishmanization using Leishmania major produced under GMP guideline is a valuable tool to protect against CL, there are limitations which need further study.


Assuntos
Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/prevenção & controle , Vacinas Protozoárias/imunologia , Vacinas Protozoárias/uso terapêutico , Vacinação/métodos , Humanos
15.
Arch Pharm (Weinheim) ; 352(11): e1900128, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536649

RESUMO

A series of new lawsone Mannich bases derived from salicylaldehydes or nitrofurfural were prepared and tested for their activities against Leishmania major, Toxoplasma gondii, and Trypanosoma brucei brucei parasites. The hydrochloride salts 5a and 6a of the Mannich bases 2a and 3a, derived from unsubstituted salicylaldehyde and long-chained alkyl amines, were selectively and strongly active against T. gondii cells and appear to be new promising drug candidates against this parasite. Compound 6a showed an even higher activity against T. gondii than the known lawsone Mannich base 1b. Compound 4a, derived from salicylaldehyde and 2-methylaminopyridine, was also distinctly active against T. gondii cells. The derivatives 3a (salicyl derivative), 3b (3,5-dichloro-2-hydroxyphenyl derivative), and 3d (5-nitrofuranyl derivative) as well as the hydrochlorides 6a and 6b were also efficacious against T. b. brucei cells with compounds 3a and 3b being more selective for T. b. brucei over Vero cells when compared with the known control compound 1b. The derivatives 5a, 5c, 6a, and 6c proved to be up to five times more active than 1b against L. major promastigotes and up to four times more efficacious against L. major amastigotes.


Assuntos
Antiparasitários/farmacologia , Leishmania major/efeitos dos fármacos , Naftoquinonas/farmacologia , Toxoplasma/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos , Antiparasitários/síntese química , Antiparasitários/química , Relação Dose-Resposta a Droga , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
16.
J Trace Elem Med Biol ; 56: 162-168, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473559

RESUMO

BACKGROUND: The pentavalent antimonial compounds are the first drug of choice for leishmania infection, but have several side effects that cause some restriction for use. Extension of nanoparticle use in biological research and proven effectiveness of manganese nanoparticles on fungi and bacteria, along with the lack of information about its antileishmanial effects, have motivated this study. Manganese can induce cell apoptosis by increasing FOXO3a-Bim/PUMA mRNA activation and activating of caspase-3 pathway. METHODS: This study was aimed to examine the efficacy of manganese oxide nanoparticles againstLeishmania major (MRHO/IR/75/ER) in vitro and in vivo. To evaluate the antileishmanial activity of NPs, light microscopic observation was used to determine the number of remaining parasites in each well. The MTT test was used to determine the cytotoxicity effects of Mn2O3 NPs against L. major promastigotes and macrophage cells. The effect of nanoparticles on cultured amastigotes under in vitro conditions was also investigated. The possible apoptosis of L. major by Mn2O3 NPs was evaluated with flow cytometry assay. Additionally, the preventive and therapeutic effects of Mn2O3 NPs in BALB/c mice following cutaneous L. major infection was tested. The effect of Mn2O3 NPs on promastigotes and amastigotes were proven by MTT assay and amastigote assay, respectively. RESULTS: The IC50 value of Mn2O3 NPs against L. major promastigotes and macrophages was 15 and 40 µg ml-1 respectively. The results of flow cytometry showed about 57% of the promastigotes were induced to apoptosis with Mn2O3 NPs. In in vivo studies, the size of the ulcers were significantly reduced, and the survival rate of the mice, in comparison with the control group, was increased. CONCLUSION: Mn2O3 NPs has a beneficial effect on L. major promastigotes in vitro and in vivo and could be considered as a candidate for the treatment of this infection.


Assuntos
Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Compostos de Manganês/farmacologia , Nanopartículas/química , Óxidos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Leishmania major/crescimento & desenvolvimento , Leishmaniose Cutânea/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura
17.
Exp Parasitol ; 205: 107747, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442454

RESUMO

Development of new chemotherapeutic agents is an essential issue in the treatment and control of a disease. This study aimed to evaluate the anti-leishmanial activity of amiodarone, an antiarrhythmic class III drug, against Leishmania major, the most prevalent etiological agent of cutaneous leishmaniasis in the old world. The proliferation of promastigotes and intracellular amastigotes in the absence or presence of amiodarone was estimated, in an in vitro study. For in vivo study, five weeks after infection of BALB/c mice with L. major, when the lesions appeared at the injection site, the mice were divided into four groups (n = 6 each); treatment was conducted for 28 consecutive days with vehicle, amiodarone at 40 mg/kg orally and glucantime at 60 mg/kg intraperitoneally. Therapy with amiodarone reduced the size of lesions compared to the untreated group after 12 days. Amiodarone decreased the parasite load and inflammatory responses, particularly the macrophages containing amastigotes, and enhanced granulation tissue formation in the dermis and subcutaneous area. The Tumor necrosis factor-α and Interleukin-6 levels were significantly lower in the cell culture supernatants of the inguinal lymph node in the amiodarone treated group compared to the vehicle and untreated groups. Amiodarone significantly increased the activity of glutathione peroxidase in comparison to the vehicle and untreated groups but did not affect the plasma levels of superoxide dismutase, malondialdehyde, adiponectin, and ferric reducing ability of plasma. Therefore, the anti- L. major activity and immunomodulatory effects of amiodarone reduced the parasitic load and enhanced wound healing in cutaneous leishmaniasis in BALB/c mice. Amiodarone reduced the lesion surface area, but it did not cure it completely.


Assuntos
Amiodarona/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Adiponectina/sangue , Amiodarona/farmacologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiprotozoários/farmacologia , Linhagem Celular , Feminino , Glutationa Peroxidase/metabolismo , Concentração Inibidora 50 , Interleucina-6/análise , Leishmania major/ultraestrutura , Leishmaniose Cutânea/parasitologia , Linfonodos/química , Linfonodos/imunologia , Macrófagos/parasitologia , Malondialdeído/sangue , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Distribuição Aleatória , Pele/parasitologia , Pele/patologia , Pele/ultraestrutura , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/análise
18.
Exp Parasitol ; 204: 107728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348915

RESUMO

BACKGROUND: Co-infection with Leishmania major and Schistosoma mansoni may have significant consequences for disease progression, severity and subsequent transmission dynamics. Pentavalent antimonials and Praziquantel (PZQ) are used as first line of treatment for Leishmania and Schistosoma infections respectively. However, there is limited insight on how combined therapy with the standard drugs impacts the host in comorbidity. The study aimed to determine the efficacy of combined chemotherapy using Pentostam (P) and PZQ in murine model co-infected with L. major and S. mansoni. METHODS: A 3 × 4 factorial design with three parasite infection groups (Lm, Sm, Lm + Sm to represent L. major, S. mansoni and L. major + S. mansoni respectively) and four treatment regimens [P, PZQ, P + PZQ, and PBS designating Pentostam (GlaxoSmithKline UK), Praziquantel (Biltricide®, Bayer Ag. Leverkusen, Germany), Pentostam + Praziquantel and Phosphate buffered saline] as factors was applied. RESULTS: Significant changes were observed in the serum Interferon gamma (IFN-γ), and Macrophage inflammatory protein-one alpha (MIP-1α) levels among various treatment groups between week 8 and week 10 (p < 0.05). There was increased IFN-γ in the L. major infected mice subjected to PZQ and PBS, and in L. major + S. mansoni infected BALB/c mice treated with P + PZQ. Subsequently, MIP-1α levels increased significantly in both the L. major infected mice under PZQ and PBS and in L. major + S. mansoni infected BALB/c mice undergoing concurrent chemotherapy with P + PZQ between 8 and 10 weeks (p < 0.05). In the comorbidity, simultaneous chemotherapy resulted in less severe histopathological effects in the liver. CONCLUSION: It was evident, combined first line of treatment is a more effective strategy in managing co-infection of L. major and S. mansoni. The findings denote simultaneous chemotherapy compliments immunomodulation in the helminth-protozoa comorbidity hence, less severe pathological effects following the parasites infection. Recent cases of increased incidences of polyparasitism in vertebrates call for better ways to manage co-infections. The findings presented necessitate intrinsic biological interest on examining optimal combined chemotherapeutic agents strategies in helminth-protozoa concomitance and the related infections abatement trends vis-a-vis host-parasite relationships.


Assuntos
Anti-Helmínticos/uso terapêutico , Antiprotozoários/uso terapêutico , Comorbidade , Leishmania major/patogenicidade , Leishmaniose Cutânea/complicações , Esquistossomose mansoni/complicações , Análise de Variância , Animais , Anti-Helmínticos/administração & dosagem , Gluconato de Antimônio e Sódio/administração & dosagem , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/administração & dosagem , Quimiocina CCL3/sangue , Modelos Animais de Doenças , Quimioterapia Combinada , Interferon gama/sangue , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Fígado/parasitologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Praziquantel/administração & dosagem , Praziquantel/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/patologia
19.
Eur J Med Chem ; 179: 335-346, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260888

RESUMO

Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazide derivatives. Based on a structure-guided approach, they were designed to possess anti-leishmanial activity through anti-folate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro anti-promastigote and anti-amastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine. The most active compounds 8i and 8j exhibited their anti-amastigote activity with IC50 values of 4.2 and 3.3 µM, respectively, compared to reference miltefosine (IC50 value of 7.3). Their anti-folate mechanism was confirmed via the ability of folic and folinic acids to reverse the anti-leishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Interestingly, the in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells. Furthermore, the docking experiments on Lm-PTR1 as a putative target rationalized the in vitro anti-leishmanial activity. The in silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. Generally, this work introduces a fruitful matrix for new anti-leishmanial chemotype which would extend the chemical space for the anti-leishmanial activity.


Assuntos
Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Ácidos Nicotínicos/farmacologia , Semicarbazidas/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Leishmania major/crescimento & desenvolvimento , Modelos Moleculares , Estrutura Molecular , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/química , Testes de Sensibilidade Parasitária , Semicarbazidas/química , Relação Estrutura-Atividade , Células Vero
20.
Int J Antimicrob Agents ; 54(4): 496-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323307

RESUMO

Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The World Health Organization has classed leishmaniasis as a category 1 neglected tropical disease. Leishmaniasis represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. As the use of oral treatment options such as paromomycin and miltefosine has increased, the incidence of disease relapse has increased and drug resistance to antimonials has developed, emphasizing the importance of identifying new chemotherapies. A novel, target-free fluorometric high-throughput screen with an average Z-score of 0.73 +/- 0.13 has been developed to identify small molecules with antileishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80% of parasites, resulting in a hit rate of 2.1%. One hundred and nine molecular scaffolds were represented within the hit compounds, and one scaffold that exhibited potent antileishmanial activity was 2,4-diaminoquinazoline. Host cell toxicity was determined prior to in-vitro infection of human THP-1 macrophages with Leishmania donovani mCherry expressing promastigotes; successful drug treatment was considered when the half maximal inhibitory concentration was <10 µM. BALB/c mice were infected with Leishmania major mCherry promastigotes and treated with small molecules that were successful during in-vitro infections. Several small molecules tested were as efficacious at resolving cutaneous leishmaniasis lesions in mice as known antimonial treatments.


Assuntos
Antiprotozoários/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala , Leishmania donovani/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Modelos Animais de Doenças , Feminino , Fluorometria/métodos , Humanos , Camundongos Endogâmicos BALB C , Recidiva , Células THP-1/parasitologia , Resultado do Tratamento
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