Activity of antimalarial drugs in vitro and in a murine model of cutaneous leishmaniasis

2013 ◽  
Vol 62 (7) ◽  
pp. 1001-1010 ◽  
Author(s):  
Vinícius Pinto Costa Rocha ◽  
Fabiana Regina Nonato ◽  
Elisalva Teixeira Guimarães ◽  
Luiz Antônio Rodrigues de Freitas ◽  
Milena Botelho Pereira Soares
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Parasite Burden ◽  
Lesion Size ◽  
Oral Route ◽  
Antimalarial Drugs ◽  
Endocytic Pathway ◽  
Multivesicular Bodies ◽  
Draining Lymph Nodes

The currently used treatments for leishmaniasis, a neglected parasitic disease, are associated with several side effects, high cost and resistance of the Leishmania parasites. Here we evaluated in vitro and in vivo the antileishmanial activity of five antimalarial drugs against Leishmania amazonensis. Mefloquine was effective against promastigotes in axenic cultures and showed an IC50 (concentration giving half-maximal inhibition) value of 8.4±0.7 µM. In addition, mefloquine, chloroquine and hydroxychloroquine were active against intracellular amastigotes in macrophage-infected cultures, presenting IC50 values of 1.56±0.19 µM, 0.78±0.08 µM and 0.67±0.12 µM, respectively. The ultrastructural analysis of chloroquine- or mefloquine-treated amastigotes showed an accumulation of multivesicular bodies in the cytoplasm of the parasite, suggesting endocytic pathway impairment, in addition to the formation of myelin-like figures and enlargement of the Golgi cisternae. CBA mice were infected with L. amazonensis in the ear dermis, and treated by oral and/or topical routes with chloroquine and mefloquine. Treatment of L. amazonensis-infected mice with chloroquine by the oral route reduced lesion size, which was associated with a decrease in the number of parasites in the ear, as well as the parasite burden in the draining lymph nodes. In contrast, mefloquine administration by both routes decreased the lesion size in infected mice without causing a reduction in parasite burden. Our results revealed a promising antileishmanial effect of chloroquine and suggest its use in cutaneous leishmaniasis treatment.

scholarly journals Effect of Foeniculum Vulgare Aqueous and Alcoholic Seed Extract against Zoonotic Cutaneous Leishmaniasis

2021 ◽  
Vol 31 (2) ◽  
Author(s):  
Gholamrezaei Mostafa ◽  
Jalallou Nahid ◽  
Seyyedtabaei Seyyed javad ◽  
Dadashi Alireza ◽  
Salimi Sabour Ebrahim
Keyword(s):  
Body Weight ◽  
Side Effects ◽  
Cutaneous Leishmaniasis ◽  
Parasite Burden ◽  
Lesion Size ◽  
Cytotoxicity Assay ◽  
Alcoholic Extract ◽  
Foeniculum Vulgare

BACKGROUND፡ Cutaneous leishmaniasis is considered one of the major neglected tropical diseases. Drug resistance, limitary efficacy, and severe side effects remain a challenge for treatment. Foeniculum vulgare is known as a medicinal plant belonging to the Apiaceae, and anti-microbial properties of this plant have already been confirmed.METHOD: The F.vulgare sterile aqueous and alcoholic extracts were prepared. In vitro has used RAW 264.7 cell line and L. major parasite (MRHO/IR/75/ER). Cytotoxicity assay on macrophages (CC50), cytotoxicity assay on promastigotes (IC50), and cytotoxicity assay on infected macrophages (EC50) were accomplished with both extracts by MTT and light microscopy methods. Four in vivo were allocated in four groups and five BALB/c mice each group. Stationary phase promastigotes were inoculated into the base of mice tails subcutaneously (SC).Measurement of the body weight, lesion size, parasite burden of the lesion, and spleen after 4 weeks for evaluation effects of the alcoholic extract on CL was done.RESULTS: The results of in vitro revealed that the optimal concentrations of both extracts reducing the promastigotes and amastigotes growth. Alcoholic extract no harmful side effects for the host macrophages, while were indicated has a potent action against L. major. In vivo results after 4 weeks did not show any variation in lesion size and body weight. Also, lesion size and spleen parasite burden decreased in comparison to no treatment group.CONCLUSION: The alcoholic extract could be a new alternative treatment for cutaneous leishmaniasis. However this extract needs more investigation for novel herbal drugs against CL. 

scholarly journals Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

2016 ◽  
Vol 60 (5) ◽  
pp. 2932-2940 ◽  
Author(s):  
Douglas R. Rice ◽  
Paola Vacchina ◽  
Brianna Norris-Mullins ◽  
Miguel A. Morales ◽  
Bradley D. Smith
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Coordination Complexes ◽  
Chemotherapeutic Agents ◽  
Selective Toxicity ◽  
Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

In vivo efficacy of meglumine antimoniate-loaded nanoparticles for cutaneous leishmaniasis: a systematic review

Nanomedicine ◽  
2021 ◽  
Author(s):  
Meliana Borilli Pereira ◽  
Bruna Gomes Sydor ◽  
Karla Gabriela Memare ◽  
Thaís Gomes Verzignassi Silveira ◽  
Sandra Mara Alessi Aristides ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Polymeric Nanoparticles ◽  
Parasite Burden ◽  
Lesion Size ◽  
Eligibility Criteria ◽  
Meglumine Antimoniate ◽  
In Vivo Experiments

Background: Nanotechnology is a promising strategy to improve existing antileishmanial agents. Objective: To explore the evidence of encapsulated meglumine antimoniate for cutaneous leishmaniasis treatment in animal models. Materials & methods: The studies were recovered from PubMed, Scopus, EMBASE, LILACS, WoS and Google according to eligibility criteria following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Population, Intervention, Comparison, Outcomes and Study design (PICOS) strategy. Study appraisal was assessed using the Animal Research Reporting of In Vivo Experiments, SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) recommendations. Results: Five studies were included. Liposomes, metallic and polymeric nanoparticles were tested in BALB/c mice against Leishmania major, L. tropica or L. amazonensis. Limitations: Few studies were found to meet the eligibility criteria. Conclusion: All formulations had a significant efficacy, similar to the meglumine antimoniate reference treatment concerning the lesion size and parasite burden. The studies had a high and moderate risk of bias, and the confidence in cumulative evidence was considered low. Therefore, we encourage the development of high-quality preclinical studies. Registration: PROSPERO register CRD42020170191.

scholarly journals Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1394 ◽  
Author(s):  
Pablo Bilbao-Ramos ◽  
Dolores R. Serrano ◽  
Helga Karina Ruiz Saldaña ◽  
Juan J. Torrado ◽  
Francisco Bolás-Fernández ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Chronic Infection ◽  
Acute Infection ◽  
Parasite Burden ◽  
Immunological Response ◽  
Lesion Size ◽  
Experimental Models ◽  
Infection Model

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

Topical tamoxifen in the therapy of cutaneous leishmaniasis

Parasitology ◽  
2017 ◽  
Vol 145 (4) ◽  
pp. 490-496 ◽  
Author(s):  
CRISTIANA T. TRINCONI ◽  
JULIANA Q. REIMÃO ◽  
VIVIAN I. BONANO ◽  
CAROLINE R. ESPADA ◽  
DANILO C. MIGUEL ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Experimental Model ◽  
Treatment Efficacy ◽  
Therapeutic Efficacy ◽  
Parasite Burden ◽  
Lesion Size ◽  
Leishmania Amazonensis ◽  
End Of Treatment

SUMMARYThe aims of the present work were to test the effect of tamoxifen administered topically and the therapeutic efficacy of tamoxifen and pentavalent antimonial combinations in an experimental model of cutaneous leishmaniasis. BALB/c mice infected with a luciferase expressing line of Leishmania amazonensis were treated with topical tamoxifen in two different formulations (ethanol or oil-free cream) as monotherapy or in co-administration with pentavalent antimonial. Treatment efficacy was evaluated by lesion size and parasite burden, quantified through luminescence, at the end of treatment and 4 weeks later. Topical tamoxifen, formulated in ethanol or as a cream, was shown to be effective. The interaction between tamoxifen and pentavalent antimonial was additive in vitro. Treatment with combined schemes containing tamoxifen and pentavalent antimonial was effective in reducing lesion size and parasite burden. Co-administration of tamoxifen and pentavalent antimonial was superior to monotherapy with antimonial.

scholarly journals In Vitro and In Vivo Anti-Parasitic Activity of Artemisinin Combined With Glucantime and Shark Cartilage Extract on Iranian Strain of Leishmania major (MRHO/IR/75/ER)

2021 ◽  
Vol 14 (3) ◽  
Author(s):  
Fatemeh Ghaffarifar ◽  
Soheila Molaei ◽  
Zuhair Mohammad Hassan ◽  
Mohammad Saaid Dayer ◽  
Abdolhossein Dalimi ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Human Subjects ◽  
Parasite Burden ◽  
Lesion Size ◽  
In Vivo Experiments ◽  
Parasitic Activity ◽  
Shark Cartilage ◽  
Immune System Modulation

Background: The adverse effects and increased resistance of drugs necessities the discovery of novel combination therapy. Objectives: This study aimed to examine the effects of Artemisinin plus glucantime or shark cartilage extract on the Iranian strain of Leishmania major (MRHO/IR/75/ER) in vitro and in vivo. Methods: In in vitro experiments, the effects of drugs and their combination in different concentrations (3.12 - 400 µg/mL) on the promastigotes, amastigotes, and un-infected macrophage cells were evaluated. In in vivo experiments, infected BALB/c mice were used as a cutaneous leishmaniasis model to evaluate the effects of the drugs and their combinations with different routes of administrations (namely Artemisinin: oral, ointment, and intraperitoneal; glucantime: intraperitoneal, intramuscular, intralesional, and subcutaneous; shark cartilage extract: oral) on parasite burden, lesion size, and immune system modulation. Results: The results revealed that Artemisinin and glucantime in combination with shark cartilage extract had greater effects on promastigotes than either Artemisinin or glucantime (P < 0.05), and that the combinations also had high cytotoxic effects on promastigotes and uninfected macrophages (P = 0.001). These combinations had more inhibitory effects on amastigotes and infected macrophages than promastigotes. The lesion sizes and parasite burden in the spleen decreased against the combinations of the drugs in different administrations. It was also noticed that the best combination administration route of Artemisinin and glucantime, as strong inducers of INF-γ and Th1 immune response, were ointment and IM, respectively (P < 0.05). Conclusions: The findings indicate that Artemisinin- glucantime or Artemisinin- Shark cartilage combinations are effective inhibitors of L. major. However, further clinical trials are recommended to evaluate the effects of these combinations in human subjects.

scholarly journals Chemistry and Leishmanicidal Activity of the Essential Oil from Artemisia absinthium from Cuba

2014 ◽  
Vol 9 (12) ◽  
pp. 1934578X1400901 ◽  
Author(s):  
Lianet Monzote ◽  
Abel Piñón ◽  
Ramón Scull ◽  
William N. Setzer
Keyword(s):  
Chemical Analysis ◽  
Essential Oil ◽  
Parasite Burden ◽  
Chemical Characterization ◽  
Lesion Size ◽  
Artemisia Absinthium ◽  
Main Component ◽  
Promising Source

Historically, natural products have been a rich source of lead molecules in drug discovery. In particular, products to treat infectious diseases have been developed and several reports about potentialities of essential oils (EO) against Leishmania could be found. In this study, we report the chemical characterization, anti-leishmanial effects and cytotoxicity of the EO from Artemisia absinthium L. Chemical analysis revealed the EO to be composed of 18 compounds, 11 of which were identified, accounting for 64.1% of the composition. The main component of the EO was trans-sabinyl acetate, which made up 36.7%. In vitro anti-leishmanial screening showed that the A. absinthium EO inhibited the growth of promastigotes (14.4 ± 3.6 μg/mL) and amastigotes (13.4 ± 2.4 μg/mL) of L. amazonensis; while cytotoxicity evaluation caused 6 fold higher values than those for the parasites. In a model of experimental cutaneous leishmaniasis in BALB/c mice, five doses of EO at 30 mg/kg by intralesional route demonstrated control of lesion size and parasite burden ( p< 0.05) compared with animals treated with glucantime and untreated mice. In conclusion, in vitro and in vivo results showed the potential of EO from A. absinthium as a promising source for lead or active compounds against Leishmania, which could be explored.

scholarly journals Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 607
Author(s):  
Moreno ◽  
Calvo ◽  
Schwartz ◽  
Navarro-Blasco ◽  
González-Peñas ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Ex Vivo ◽  
Skin Permeation ◽  
Topical Therapy ◽  
Parasite Burden ◽  
Skin Penetration ◽  
High Plasma

The oral administration of dapsone (DAP) for the treatment of cutaneous leishmaniasis (CL) is effective, although serious hematological side effects limit its use. In this study, we evaluated this drug for the topical treatment of CL. As efficacy depends on potency and skin penetration, we first determined its antileishmanial activity (IC50 = 100 μM) and selectivity index in vitro against Leishmania major-infected macrophages. In order to evaluate the skin penetration ex vivo, we compared an O/W cream containing DAP that had been micronized with a pluronic lecithin emulgel, in which the drug was solubilized with diethylene glycol monoethyl ether. For both formulations we obtained similar low flux values that increased when the stratum corneum and the epidermis were removed. In vivo efficacy studies performed on L. major-infected BALB/c mice revealed that treatment not only failed to cure the lesions but made their evolution and appearance worse. High plasma drug levels were detected and were concomitant with anemia and iron accumulation in the spleen. This side effect was correlated with a reduction of parasite burden in this organ. Our results evidenced that DAP in these formulations does not have an adequate safety index for use in the topical therapy of CL.

scholarly journals In VitroandIn VivoStudies of the Utility of Dimethyl and Diethyl Carbaporphyrin Ketals in Treatment of Cutaneous Leishmaniasis

2011 ◽  
Vol 55 (10) ◽  
pp. 4755-4764 ◽  
Author(s):  
Viviana M. Taylor ◽  
David L. Cedeño ◽  
Diana L. Muñoz ◽  
Marjorie A. Jones ◽  
Timothy D. Lash ◽  
...  
Keyword(s):  
Visible Light ◽  
Cutaneous Leishmaniasis ◽  
Peritoneal Macrophages ◽  
Lesion Size ◽  
Content Type ◽  
Content Model ◽  
Parasitic Load ◽  
Micromolar Range

ABSTRACTCarbaporphyrin ketals are porphyrinoid compounds in which a pyrrole ring of a typical porphyrin macrocycle has been replaced by a ketal-substituted indene ring. It was recently demonstrated that these compounds are effectivein vitroagainstLeishmania tarentolae. Theirin vitroeffectiveness is increased when they are exposed to visible light; they act as photosensitizers capable of mediating the production of reactive oxygen species (ROS). Following on this evidence, the effectiveness and cytotoxicity of the dimethyl and diethyl carbaporphyrin ketals (CKOMe and CKOEt, respectively) were determinedin vitrousing pathogenicLeishmaniaspecies with and without exposure to visible light (2 and 4 h). The effectiveness against various pathogenicLeishmaniaspecies was determined to be in a micromolar range. Additionally, the effect of encapsulating the carbaporphyrin ketals in liposome formulations was tested. Liposomal delivery diminished their toxicity, while the effectiveness was enhanced upon exposure to visible light (photodynamic effect). The cytotoxicity levels for human U937 cells and hamster peritoneal macrophages were in the ranges of 0.3 to 9 μM and 7 to 330 μM, respectively. When testedin vivo, using a hamster (Mesocricetus auratus) model of cutaneous leishmaniasis, CKOMe was active even in the dark, suggesting that the compound, once metabolized in the animal tissue, produces an active ingredient that does not seem to be photosensitive. Reduction in lesion size, histopathologic analyses, and smears confirmed thein vivo effectiveness of the compound, since the parasitic load was diminished without noticeable toxic effects.

scholarly journals MicroRNAs Expression Induces Apoptosis of Macrophages in Response to Leishmania major (MRHO/IR/75/ER): An In-Vitro and In-Vivo Study

2020 ◽  
Author(s):  
Mostafa GHOLAMREZAEI ◽  
Soheila ROUHANI ◽  
Mehdi MOHEBALI ◽  
Samira MOHAMMADI-YEGANEH ◽  
Mostafa HAJI MOLLA HOSEINI ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Parasite Load ◽  
Lesion Size ◽  
In Vivo Studies ◽  
Raw 264.7 Cells ◽  
Control Group

Background: We aimed to investigate the effect of miR-15a mimic and inhibitor of miR-155 expression on apoptosis induction in macrophages infected with Iranian strain of Leishmania major in-vitro and in-vivo. Methods: RAW 264.7 cells were infected with L. major promastigotes (MRHO/IR/75/ER), and then were treated with miRNAs. For in-vivo experiment, BALB/c mice were inoculated with L. major promastigotes, and then they were treated with miRNAs. For evaluation of miRNA therapeutic effect, in-vitro and in-vivo studies were performed using quantitative Real-time PCR, Flow cytometry, lesion size measurement, and Limiting Dilution Assay (LDA). This study was performed in Shahid Beheshti University of Medical Sciences in 2019. Results: In-vitro results of flow cytometry showed that using miR-15a mimic, miR-155 inhibitor or both of them increased apoptosis of macrophages. In in-vivo, size of lesion increased during experiment in control groups (P<0.05) while application of both miR-155 inhibitor and miR-15a mimic inhibited the increase in the size of lesions within 6 wk of experiment (P=0.85). LDA results showed that microRNA therapy could significantly decrease parasite load in mimic or inhibitor receiving groups compared to the control group (P<0.05). Conclusion: miR-155 inhibitor and miR-15a mimic in L. major infected macrophages can induce apoptosis and reduce parasite burden. Therefore, miRNA-based therapy can be proposed as new treatment for cutaneous leishmaniasis.

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