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 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 Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

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.

Effectiveness of doxycycline for the treatment of zoonotic cutaneous leishmaniasis in vivo

Parasitology ◽  
2020 ◽  
pp. 1-5
Author(s):  
Iuliia K. Akulinina ◽  
Iza A. Berechikidze ◽  
Svetlana N. Larina ◽  
Tatyana V. Sakharova ◽  
Tatyana Yu. Degtyarevskaya ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Body Weight Gain ◽  
Laboratory Model ◽  
Meglumine Antimoniate ◽  
Virulent Strains ◽  
Zoonotic Cutaneous Leishmaniasis ◽  
Highly Virulent ◽  
Average Body

Abstract There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with meglumine antimoniate (glucantime). We used golden Syrian hamsters as a laboratory model. Experimental groups were formed, each of which was treated with one of the tested drugs. Infection of animals was carried out with Leishmania major promastigotes. We selected highly virulent strains of L. major culture isolated from human ulcers or rodents. Meglumine antimoniate monotherapy and doxycycline monotherapy are quite effective and do not differ by the 30th day of their use in such indicators as the average degree of local damage and the average number of Leishmania in the lesions. The main differences were recorded in terms of average body weight gain and average clinical recovery in favour of doxycycline. Leishmania in the lesion on the 60th day were completely absent in treatment with doxycycline. The experiment proved the effectiveness of doxycycline monotherapy: Leishmania in the lesions were absolutely absent by the end of the treatment.

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 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 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.

scholarly journals Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation

2021 ◽  
Vol 15 (7) ◽  
pp. e0009638
Author(s):  
Ellen Heirwegh ◽  
Emily MacLean ◽  
Jinlei He ◽  
Shaden Kamhawi ◽  
Selena M. Sagan ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Myeloid Cell ◽  
Skin Lesions ◽  
Health Concern ◽  
Global Public Health ◽  
Knock Out

Background The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. Methodology/Principal findings In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV’s hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. Conclusion/Significance Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.

scholarly journals Topical Treatment for Cutaneous Leishmaniasis: Dermato-Pharmacokinetic Lead Optimization of Benzoxaboroles

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Katrien Van Bocxlaer ◽  
Eric Gaukel ◽  
Deirdre Hauser ◽  
Seong Hee Park ◽  
Sara Schock ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Skin Permeation ◽  
Mouse Skin ◽  
Topical Administration ◽  
Lesion Size ◽  
Drug Formulation ◽  
Content Type

ABSTRACTCutaneous leishmaniasis (CL) is caused by several species of the protozoan parasiteLeishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 μM) against intracellular amastigotes of at least oneLeishmaniaspecies and acceptable activity (20 μM < EC50< 30 μM) against two more species. Benzoxaborole compounds were further prioritized on the basis of thein vitroevaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that ofpara-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) againstLeishmania majorwas testedin vivo. LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.

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