Moreno-Amatria, E. (Esther)
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- Assesment of β-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB/c mice(Elsevier, 2015) Larrea, E. (Esther); Sanmartin-Grijalba, C. (Carmen); Font, M. (María); Schwartz, J. (Juana); Conde, I. (Iosune); Espuelas, S. (Socorro); Moreno-Amatria, E. (Esther); Irache, J.M. (Juan Manuel)Abstract Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of β-lapachone (β- LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. The loading of β-LP in lecithin-chitosan NP was critical to achieve important drug accumulation in the dermis and permeation through the skin. In addition, it did not influence the drug antileishmanial activity. When topically applied in L. major infected BALB/c mice, 2 β-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopatological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that β-LP exhibited anti-inflammatory activity leading to the downregulation of IL-1β and COX-2 expression and a decrease of neutrophils infiltrate.
- Library of Seleno-Compounds as Novel Agents against Leishmania Species(2017) Alcolea-Devesa, V. (Verónica); Gutierrez-Sanchez, R. (Ramon); Sanmartin-Grijalba, C. (Carmen); Martin-Escolano, R. (Ruben); Pérez-Silanes, S. (Silvia); Sanchez-Moreno, M. (Manuel); Plano-Amatriain, D. (Daniel); Espuelas, S. (Socorro); Marin, C. (Clotilde); Diaz, M. (Marta); Moreno-Amatria, E. (Esther); Martin-Montes, A.(Alvaro)The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.
- Evaluation of skin permeation and retention of topical dapsone in murine cutaneous leishmaniasis lesions(2019) Sanmartin-Grijalba, C. (Carmen); Schwartz, J. (Juana); Calvo-Bacaicoa, A. (Alba); Gonzalez-Peñas, E. (Elena); Espuelas, S. (Socorro); Navarro-Blasco, I. (Iñigo); Moreno-Amatria, E. (Esther); Irache, J.M. (Juan Manuel)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 ¿M) 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.
- Repurposing the antibacterial agents peptide 19-4LF and peptide 19-2.5 for treatment of cutaneous leishmaniasis(2022) Peña-Guerrero, J. (José); Brandenburg, K. (Klaus); Larrea, E. (Esther); Abdel-Sater, F. (Fadi); Espuelas, S. (Socorro); Martinez-de-Tejada, G. (Guillermo); El-Dirany, R. (Rima); Moreno-Amatria, E. (Esther); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-¿, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed ...
- Oral efficacy of a diselenide compound loaded in nanostructured lipid carriers in a murine model of visceral leishmaniasis(2021) Almeida, A.J. (Antonio J.); Alvarez-Galindo, J.I. (José Ignacio); Sanmartin-Grijalba, C. (Carmen); Etxebeste-Mitxeltorena, M. (Mikel); Calvo-Bacaicoa, A. (Alba); Plano-Amatriain, D. (Daniel); Gonzalez-Peñas, E. (Elena); Espuelas, S. (Socorro); Carvalheiro, M. (Manuela); Navarro-Blasco, I. (Iñigo); Moreno-Amatria, E. (Esther); Irache, J.M. (Juan Manuel)Leishmaniasis urgently needs new oral treatments, as it is one of the most important neglected tropical diseases that affects people with poor resources. The drug discovery pipeline for oral administration currently discards entities with poor aqueous solubility and permeability (class IV compounds in the Biopharmaceutical Classification System, BCS) such as the diselenide 2m, a trypanothione reductase (TR) inhibitor. This work was assisted by glyceryl palmitostearate and diethylene glycol monoethyl ether-based nanostructured lipid carriers (NLC) to render 2m bioavailable and effective after its oral administration. The loading of 2m in NLC drastically enhanced its intestinal permeability and provided plasmatic levels higher than its effective concentration (IC50). In L. infantum-infected BALB/c mice, 2m-NLC reduced the parasite burden in the spleen, liver, and bone marrow by at least 95% after 5 doses, demonstrating similar efficacy as intravenous Fungizone. Overall, compound 2m and its formulation merit further investigation as an oral treatment for visceral leishmaniasis.
- New amides and phosphoramidates containing selenium: studies on their cytotoxicity and antioxidant activities in breast cancer(2021) Aydillo-Miguel, C. (Carlos); Sanmartin-Grijalba, C. (Carmen); Morán-Serradilla, C. (Cristina); Encío, I. (Ignacio); Etxebeste-Mitxeltorena, M. (Mikel); Plano-Amatriain, D. (Daniel); Espuelas, S. (Socorro); Moreno-Amatria, E. (Esther); Astráin-Redín, N. (Nora)Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 mu M, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d.
- Diseño, síntesis y evaluación biológica de nuevos derivados de pirido[2,3-d] pirimidina y quinazolina con actividad antitumoral. Valoración de su capacidad antimetastática(Servicio de Publicaciones de la Universidad de Navarra, 2013) Moreno-Amatria, E. (Esther); Palop-Cubillo, J.A. (Juan Antonio); Sanmartin-Grijalba, C. (Carmen)The disease of cancer has been ranked as a major health burden. Pyrido[2,3-d]pyrimidine and quinazoline derivatives have attracted attention due to their broad range of pharmacological activities: antifungal, antimalarial, anti-inflammatory, anticonvulsant, antibacterial, antihypertensive, and their anticancer activity is one of the most promising aspects as they act through multiple targets. Based on these observations and considering our experience with these heteroaromatic rings, we have synthesized 57 novel 2.4-disubstituted quinazoline and Pyrido[2,3-d]pyrimidine derivatives. These compounds have been screened in vitro against five tumoral cell lines – prostate (PC-3), leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) – and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 have been the most sensitive cell lines with GI50 values below 10 µM for eleven and ten compounds, respectively. To compounds (I.3 and IV.14) evoke a marked cytotoxic effect in all cell lines tested and one compound, IV.7, has been potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives I.3, IV.7 andIV.14 indicates that the cytotoxic activities of these compounds might be mediated by inducing cell death without modifications on cell cycle. Moreover, the signalling pathway implicated in the cell death observed upon treatment in MCF-7 cells by compound IV.14 could be AKT/S6 ribosomal/m-TOR. The lead compounds induce inhibition of cell migration in MDA-MB-231 cells and in this inhibition of migration the kinases AKT, S6 ribosomal, FAK and SRC are not implicated.
- New cosmetic formulation for the treatment of mild to moderate infantile atopic dermatitis(MDPI, 2019) Pérez-Davó, A. (Azahara); García-Millán, C. (Cristina); Lucas, R. (Raúl) de; Moreno-Amatria, E. (Esther); Redondo-Bellón, P. (Pedro)Atopic dermatitis (AD) is a chronic cutaneous inflammatory disorder, characterized by skin barrier disruption. Dermacare is a new cosmetic formulation, which enhances moisturization, reinforces and repairs the skin barrier, and prevents cutaneous microbiota imbalance. To demonstrate its safety and efficacy, a prospective, open-label, and multicenter study was carried out on patients diagnosed with mild to moderate AD. Transepidermal water loss (TEWL), clinical severity, Desquamation Index, Patient/Investigator Global Assessments, quality of life index, and tolerance were assessed. Adverse events were recorded. Daily application of the new treatment was well tolerated, and adverse events were absent. After 14 days, TEWL showed a 36.7% significant decrease (p = 0.035). At the end of the 28-day treatment, the Desquamation Index showed a reduction in 70% of patients; Eczema Area and Severity Index were reduced by 70.4% (p = 0.002); and skin irritation showed a significant reduction (p = 0.024). Likewise, Patient and Investigator Global Assessments reported a significant improvement in conditions and an overall global worsening when patients restarted their normal treatment. Parent’s Index of Quality of Life Index significantly increased by 36.4% (p < 0.05) with Dermacare. In conclusion, a regular use of this new formulation can reduce the risk of relapse and extend the steroid-free treatment periods.