Investigation of anti-leishmanial efficacy of miltefosine and ketoconazole loaded on nanoniosomes

Nazari-Vanani, R.; Vais, R. Dehdari; Sharifi, Farshad; Sattarahmady, N.; Karimian, Khashayar; Motazedian, Mohammad Hossein; Heli, H.

doi:10.1016/j.actatropica.2018.05.002

Cited by 33 publications

(13 citation statements)

References 32 publications

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“…A large number of antitumoral compounds have demonstrated activity to treat the disease, 3,4 although the only oral drug reported to have an effect against Leishmania parasite is miltefosine (MF), an alkylphospholipid originally developed for breast cancer treatment. 5,6 When compared to the current first-line therapies, MF is more cost-effective, 7 and several studies have suggested its application against leishmaniasis using different formulations. [8][9][10][11][12][13][14][15] However, it exhibits dose-limiting gastrointestinal side effects in patients 16 because MF penetration through lipophilic barriers is reduced due to its poor aqueous solubility with the formation highly hemolytic micelles at low concentration, which easily disaggregate under oral or intravenous administration.…”

Section: Introductionmentioning

confidence: 99%

Structural characterization by scattering and spectroscopic methods and biological evaluation of polymeric micelles of poloxamines and TPGS as nanocarriers for miltefosine delivery

Puig-Rigall

Fernández-Rubio

González‐Benito

et al. 2020

International Journal of Pharmaceutics

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Section: Introductionmentioning

confidence: 99%

Structural characterization by scattering and spectroscopic methods and biological evaluation of polymeric micelles of poloxamines and TPGS as nanocarriers for miltefosine delivery

Puig-Rigall

Fernández-Rubio

González‐Benito

et al. 2020

International Journal of Pharmaceutics

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“…External test set II was built using the 139 EC 50 confirmed active compounds from the PubChem AID 2008 dataset to which the inactive compounds of the external test set I were added. Additionally to this 139 active compounds, we added to external test set II a list of 10 commercially available compounds, which are currently used in antileishmanial therapy: Allopurinol, , Amphotericin B, ,, Azithromycin, , Itraconazole, , Ketoconazole, , Metronidazole, , Miltefosine, ,,− Paromomycin, , Pentoxifylline, , and Rifampicin. ,, These 10 compounds were also subtracted from training, internal test, and external test I sets. A summary of data distribution indicating the number of active and inactive compounds in training, test, and external sets is presented in Table .…”

Section: Resultsmentioning

confidence: 99%

A Novel Automated Framework for QSAR Modeling of Highly Imbalanced Leishmania High-Throughput Screening Data

Casanova-Alvarez

Helguera

Cabrera‐Pérez

et al. 2021

J. Chem. Inf. Model.

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In silico prediction of antileishmanial activity using quantitative structure−activity relationship (QSAR) models has been developed on limited and small datasets. Nowadays, the availability of large and diverse high-throughput screening data provides an opportunity to the scientific community to model this activity from the chemical structure. In this study, we present the first KNIME automated workflow to modeling a large, diverse, and highly imbalanced dataset of compounds with antileishmanial activity. Because the data is strongly biased toward inactive compounds, a novel strategy was implemented based on the selection of different balanced training sets and a further consensus model using single decision trees as the base model and three criteria for output combinations. The decision tree consensus was adopted after comparing its classification performance to consensuses built upon Gaussian-Naıve-Bayes, Support-Vector-Machine, Random-Forest, Gradient-Boost, and Multi-Layer-Perceptron base models. All these consensuses were rigorously validated using internal and external test validation sets and were compared against each other using Friedman and Bonferroni−Dunn statistics. For the retained decision tree-based consensus model, which covers 100% of the chemical space of the dataset and with the lowest consensus level, the overall accuracy statistics for test and external sets were between 71 and 74% and 71 and 76%, respectively, while for a reduced chemical space (21%) and with an incremental consensus level, the accuracy statistics were substantially improved with values for the test and external sets between 86 and 92% and 88 and 92%, respectively. These results highlight the relevance of the consensus model to prioritize a relatively small set of active compounds with high prediction sensitivity using the Incremental Consensus at high level values or to predict as many compounds as possible, lowering the level of Incremental Consensus. Finally, the workflow developed eliminates human bias, improves the procedure reproducibility, and allows other researchers to reproduce our design and use it in their own QSAR problems.

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“…The IC 50 value of KETO against J774A.1 cells was previously reported as 351 μg/mL, which is quite high as compared to our finding (17 μg/mL). 40 Thus, the explored formulation could be promising to reduce fungal cells or amastigotes without causing normal cell toxicity. 40 Figure 4B shows the cellular uptake by the infected cells (candida) using various concentrations of K30G.…”

Section: ■ Methodsmentioning

confidence: 99%

Improved Subcutaneous Delivery of Ketoconazole Using EpiDerm and HSPiP Software-Based Simulations as Assessed by Cell Viability, Cellular Uptake, Permeation, and Hemolysis In Vitro Studies

et al. 2022

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Ketoconazole (KETO) is the drug of choice to control local, systemic, and resistant types of fungal infections. Subcutaneous (sub-Q) delivery offers several benefits. The present study investigated the sub-Q delivery of KETO using HSPiP software based on optimized concentrations of dimethylacetamide (DMA) in binary solvents (DMA + water), in vitro cellular uptake (J774A.1) assays, cellular toxicity (L929), and in vitro hemolysis studies. Results showed that the estimated permeation coefficient (9.6 × 10 −3 cm/h) and diffusion coefficient (3.9 × 10 −3 cm 2 /h) of KETO (22.3 mg) in KF3 (300 mg of DMA + water) across EpiDerm were relatively higher as compared to the other formulations [KF1 (11.2 and 150 mg as KETO and DMA, respectively) and KF2 [(22.3 and 300 mg as KETO and DMA, respectively)] due to the increased content of DMA and KETO. HSPiP simulated and predicted the impact of constant and variable diffusion coefficients on the percent drug absorption across EpiDerm and the time needed to achieve equilibrium. The concentration-dependent diffusion coefficient fed into HSPiP predicted that the drug absorption and permeation values were linearly dependent on the square root of time. The HSPiP predicted permeation flux values from KF3, KF2, and KF1 across the EpiDerm were 4.07 × 10 −6 , 4.01 × 10 −6 , and 1.1 × 10 −6 g/cm 2 /s, respectively, at respective D range values. The selected K30G (324 mOsm/Kg) showed an optimal pH (6.9) and minimum drug loss (0.01%) over a period of 1 month at room temperature. KG30 was found to be less toxic to normal L292 cells and caused maximum cytotoxicity to candida cells residing within infected macrophage cells (J774A.1 incubated for 24 h), which was attributed to the slow diffusion of K30G compared to DS (the drug solution with an equivalent concentration). KG30 elicited substantial internalization with candida albicans (MTCC 4748) compared to the control group (24 h). Lastly, in vitro hemolysis studies (1 and 5 μg/mL) corroborated the safety of K30G for sub-Q delivery. Therefore, this new formulation and approach for delivering KETO is a promising alternative to conventional products to control fungal infections and, thus, should be further studied in vivo.

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Investigation of anti-leishmanial efficacy of miltefosine and ketoconazole loaded on nanoniosomes

Cited by 33 publications

References 32 publications

Structural characterization by scattering and spectroscopic methods and biological evaluation of polymeric micelles of poloxamines and TPGS as nanocarriers for miltefosine delivery

Structural characterization by scattering and spectroscopic methods and biological evaluation of polymeric micelles of poloxamines and TPGS as nanocarriers for miltefosine delivery

A Novel Automated Framework for QSAR Modeling of Highly Imbalanced Leishmania High-Throughput Screening Data

Improved Subcutaneous Delivery of Ketoconazole Using EpiDerm and HSPiP Software-Based Simulations as Assessed by Cell Viability, Cellular Uptake, Permeation, and Hemolysis In Vitro Studies

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