scholarly journals The New Pyrazolyltetrazole Derivative MSN20 Is Effective via Oral Delivery against Cutaneous Leishmaniasis

2014 ◽  
Vol 58 (10) ◽  
pp. 6290-6293 ◽  
Author(s):  
Viviane dos Santos Faiões ◽  
Maurício Silva dos Santos ◽  
Alice Maria Rolim Bernardino ◽  
Edézio Ferreira Cunha-Júnior ◽  
Marilene Marcuzzo do Canto Cavalheiro ◽  
...  
Keyword(s):  
Effective Treatment ◽  
Cutaneous Leishmaniasis ◽  
Oral Delivery ◽  
Inhibitory Concentration ◽  
Oral Treatment ◽  
Parasite Load ◽  
Leishmania Amazonensis ◽  
Lead Compound ◽  
Content Type ◽  
Medical Need

ABSTRACTAn orally delivered, safe and effective treatment for leishmaniasis is an unmet medical need. Azoles and the pyrazolylpyrimidine allopurinol present leishmanicidal activity, but their clinical efficacies are variable. Here, we describe the activity of the new pyrazolyltetrazole hybrid, 5-[5-amino-1-(4′-methoxyphenyl)1H-pyrazole-4-yl]1H-tetrazole (MSN20). MSN20 showed a 50% inhibitory concentration (IC50) of 22.3 μM against amastigotes ofLeishmania amazonensisand reduced significantly the parasite load in infected mice, suggesting its utility as a lead compound for the development of an oral treatment for leishmaniasis.

scholarly journals In Vitro and In Vivo Evaluation of an Adamantyl-Based Phenyl Sulfonyl Acetamide against Cutaneous Leishmaniasis Models of Leishmania amazonensis

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Camila C. Santos ◽  
Huaisheng Zhang ◽  
Marcos M. Batista ◽  
Gabriel M. de Oliveira ◽  
Kelly C. Demarque ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Parasite Load ◽  
Leishmania Amazonensis ◽  
Host Cells ◽  
In Vivo Evaluation ◽  
Content Type ◽  
Suboptimal Dose ◽  
Low Toxicity

ABSTRACT Phenotypic assay against Leishmania amazonensis in vitro and in vivo led to identification of an adamantyl-based phenyl sulfonyl acetamide (compound 1) as a promising antileishmanial agent. Compound 1 inhibited the growth of intracellular forms of L. amazonensis (50% inhibitory concentration [IC50] = 4 μM) and exhibited low toxicity to host cells, with a selectivity index (SI) of >125. However, in a cutaneous leishmaniasis (CL) mouse model, compound 1 did not reduce lesions and parasite load when administered as monotherapy or when given simultaneously with a suboptimal dose of miltefosine.

scholarly journals Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Simon L. Croft ◽  
Raul de la Flor ◽  
Mo Alavijeh ◽  
Vanessa Yardley ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mouse Models ◽  
Drug Exposure ◽  
Oral Treatment ◽  
Drug Application ◽  
Skin Tissue ◽  
Drug Candidate ◽  
Topical Formulation ◽  
Content Type

ABSTRACT The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative Leishmania pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL. Skin microdialysis and Franz diffusion cell permeation studies revealed that DNDI-0690 permeated poorly (<1%) into the skin lesion upon topical drug application (0.063% [wt/vol], 30 μl). In contrast, a single oral dose of 50 mg/kg of body weight resulted in the rapid and nearly complete distribution of protein-unbound DNDI-0690 from the plasma into the infected dermis (ratio of the area under the curve [0 to 6 h] of the free DNDI-0690 concentration in skin tissue to blood [fAUC0-6 h, skin tissue/fAUC0-6 h, blood] is greater than 80%). Based on in vivo bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of L. major; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.

scholarly journals In VitroCombination Studies of Benzothiazinone Lead Compound BTZ043 against Mycobacterium tuberculosis

2012 ◽  
Vol 56 (11) ◽  
pp. 5790-5793 ◽  
Author(s):  
Benoit Lechartier ◽  
Ruben C. Hartkoorn ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Bactericidal Effect ◽  
Lead Compound ◽  
Content Type ◽  
Drug Candidates ◽  
New Class ◽  
Novel Targets ◽  
Essential Enzyme ◽  
Strain H37rv

ABSTRACTBenzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates againstMycobacterium tuberculosisstrain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect onM. tuberculosisthan TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ-resistantM. tuberculosismutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen.

scholarly journals Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Katrien Van Bocxlaer ◽  
Vanessa Yardley ◽  
Andy Harris ◽  
Sudaxshina Murdan ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Parasite Load ◽  
Lesion Size ◽  
Clear Correlation ◽  
Relative Reduction ◽  
Multiple Dosing ◽  
Content Type ◽  
Drug Levels ◽  
Skin Pharmacokinetics

ABSTRACTAmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with those of the deoxycholate form of AmB (DAmB; trade name Fungizone) in murine models ofLeishmania majorCL. Drug levels at the target site (the localized lesion) 48 h after single intravenous (i.v.) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6, and 8). After single and multiple dosing, intralesional concentrations were 5- and 20-fold, respectively, higher than those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25, or 12.5 mg/kg (i.v.), there was a clear correlation between dose level, intralesional AmB concentration, and relative reduction in parasite load and lesion size (R2values of >0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation.

scholarly journals Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB/c mice reduce parasite load

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alessandra M. da Fonseca-Martins ◽  
Tadeu D. Ramos ◽  
Juliana E. S. Pratti ◽  
Luan Firmino-Cruz ◽  
Daniel Claudio Oliveira Gomes ◽  
...  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Therapeutic Potential ◽  
Parasite Burden ◽  
Parasite Load ◽  
Current Treatment ◽  
Leishmania Amazonensis ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Antigen Presenting

AbstractLeishmaniasis is a neglected disease, for which current treatment presents numerous issues. Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. In this study, we observed that L. amazonensis induced PD-1 expression on both CD4+ and CD8+ T cells and PD-L1 on dendritic cells on BALB/c mice. We tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healing L. amazonensis infection in BALB/c mice, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-γ-producing CD4+ and CD8+ T cells, respectively. Compared with infection controls, mice treated with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-Leishmania antibody (IgM, IgG, IgG1 and IgG2a) or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-β production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.

scholarly journals Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Angela Maria Arenas Velásquez ◽  
Willian Campos Ribeiro ◽  
Vutey Venn ◽  
Silvia Castelli ◽  
Mariana Santoro de Camargo ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Parasite Load ◽  
Inhibitory Effect ◽  
Peritoneal Macrophages ◽  
Leishmania Amazonensis ◽  
Content Type ◽  
Intracellular Amastigotes ◽  
Therapeutic Alternatives

ABSTRACT Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N′-dimethylbenzylamine (Hdmba) against Leishmania amazonensis. The compound [Pd(dmba)(μ-N3)]2 (CP2) inhibits promastigote growth (50% inhibitory concentration [IC50] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)

scholarly journals Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Katrien Van Bocxlaer ◽  
Vanessa Yardley ◽  
Sudaxshina Murdan ◽  
Simon L. Croft
Keyword(s):  
Combination Therapy ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Q Fever ◽  
Parasite Load ◽  
Potential Candidate ◽  
Preclinical Development ◽  
Content Type

ABSTRACT The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana. In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.

scholarly journals Draft Genome Sequences of Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) mexicana, and Leishmania (Leishmania) aethiopica, Potential Etiological Agents of Diffuse Cutaneous Leishmaniasis

2019 ◽  
Vol 8 (20) ◽  
Author(s):  
Dhwani Batra ◽  
Wuling Lin ◽  
Vidhya Narayanan ◽  
Lori A. Rowe ◽  
Mili Sheth ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Sequence Data ◽  
Draft Genome ◽  
Leishmania Amazonensis ◽  
Leishmania Mexicana ◽  
Genome Sequences ◽  
Content Type ◽  
Leishmania Aethiopica ◽  
Etiological Agents

We present here the draft genome sequences of Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) mexicana, and Leishmania (Leishmania) aethiopica, potential etiological agents of diffuse cutaneous leishmaniasis (DCL). Sequence data were obtained using PacBio and MiSeq platforms.

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