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8. Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test.

Author

Cambra-Pellejà, María, Valderas-García, Elora, Balaña-Fouce, Rafael, de la Vega, Jennifer, del Olmo, Esther, Antwi-Ekwuruke, Jennifer, Linnemann, Lara, Heepmann, Lennart, Breloer, Minka, and Martínez-Valladares, María

Subjects
NEGLECTED diseases, PARASITIC diseases, STRONGYLOIDIASIS, ROAD maps, DRUG efficacy
Abstract

Strongyloidiasis is a neglected tropical disease estimated to affect more than 600 million people worldwide. Recently, the World Health Organization road map on neglected tropical diseases 2021–2030 has put the focus on strongyloidiasis, including this disease within its mass drug administration campaigns. With the use of ivermectin in extensive treatment of all populations at-risk, identifying effective therapeutic alternatives is crucial in case ivermectin resistance arises. The objective of the present study was the development of a larval migration inhibition assay to evaluate the anthelmintic efficacy of commercial drugs and diamine and aminoalcohol derivatives against infective Strongyloides ratti third stage larvae. Through this technique, we successfully screened and estimated the in vitro anthelmintic efficacy of six commercial drugs, seven diamine derivatives and eight aminoalcohol derivatives. Unexpectedly, the half-maximal effective concentration of ivermectin and moxidectin (2.21 and 2.34 μM, respectively) were observed as the highest value obtained among all commercial drugs tested by this in vitro technique. Moreover, some diamine and aminoalcohol derivatives showed superior efficacy inhibiting S. ratti motility compared to ivermectin, with five compounds (AA23, AA34, AO2 AO7 and AO14b) also displaying selectivity indexes on HepG2 and Caco2 higher than 1. These findings underscore the potential of these derivatives as promising alternatives for strongyloidiasis treatment, warranting further investigation and in vivo efficacy assessment. Author summary: Strongyloidiasis, a parasitic infection affecting over 600 million people worldwide, is increasingly recognized in global health initiatives. Caused by the nematode Strongyloides stercoralis, it predominantly occurs in tropical and subtropical regions. Transmission results through contact with soil contaminated by infectious larvae, leading to a spectrum of clinical symptoms from mild gastrointestinal discomfort to potentially life-threatening complications, especially in individuals with weakened immune systems. Despite its designation as a neglected tropical disease, concerns regarding the development of drug resistance highlight the need to explore alternative treatment strategies. In our study, we employed innovative methods to evaluate the in vitro efficacy of various drug candidates against Strongyloides ratti larvae, representing a crucial step in identifying novel therapies for human strongyloidiasis. Our findings revealed that some of the novel compounds tested, showed superior efficacy in inhibiting parasite motility, suggesting potential benefits for patient treatment outcomes. Our study underscores the urgent need for diversified treatment approaches in combating strongyloidiasis. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Secretory IgA as biomarker for gastrointestinal nematodes natural infection in different breed sheep

Author

European Commission, Junta de Castilla y León, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Giráldez, Francisco Javier [0000-0002-0680-1541], Castilla Gómez de Agüero, Verónica, Valderas García, Elora, González del Palacio, Laura, Giráldez, Francisco Javier, Balaña-Fouce, R., Martínez Valladares, María, European Commission, Junta de Castilla y León, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Giráldez, Francisco Javier [0000-0002-0680-1541], Castilla Gómez de Agüero, Verónica, Valderas García, Elora, González del Palacio, Laura, Giráldez, Francisco Javier, Balaña-Fouce, R., and Martínez Valladares, María

Abstract

Specific IgA antibody has been shown to play an important role in resistance to gastrointestinal nematode (GIN) infections in sheep, particularly in Teladorsagia circumcincta parasitosis. In some breeds, negative associations have been shown between IgA levels and worm burden in experimentally infected sheep. In the present study, we have studied the relationship between IgA levels in naturally infected sheep (582 ewes in total; 193 younger than one year old and 389 older than one year old) and fecal egg count (FEC) in the Assaf, Castellana, and Churra breeds. ELISA assays were performed to measure IgA levels against the somatic antigen of T. circumcincta third larval stage (L3) and a 203-amino-acid fragment of the protein disulfide isomerase from the same GIN species. A multilevel random intercept model was developed to predict the infection risk according to age or breed. Spearman’s correlation rank was used for statistical analysis. The prediction model showed that breed was not an influential factor in this study, although the Assaf breed could be considered slightly more susceptible than the others. In addition, age affected the infection risk, with the young ewes more susceptible to infection than the adult groups, except for the Castellana breed, whose risk of infection was similar at all ages. The most significant positive association was found between FEC and IgA measured in the nasal secretions of young ewes using both antigens (Rho = 0.5; p = 0.00); the correlation of FEC with IgA in serum was moderately significant (Rho = 0.306; p = 0.00). Comparing both antigens, the protein disulfide isomerase antigen was less reactive than the somatic antigen from L3. In conclusion, under natural conditions, specific IgA against GIN was positively associated with FEC in sheep, with nasal secretions from young animals being the sample where this association is stronger, which, therefore, could be used as a marker of infection in further studies.

Published
2023

17. Occurrence of Leishmaniasis in Iberian wolves in Northwestern Spain

Author

Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Merino Goyenechea, J., Castilla Gómez de Agüero, Verónica, Palacios Alberti, J., Balaña-Fouce, Rafael, Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Merino Goyenechea, J., Castilla Gómez de Agüero, Verónica, Palacios Alberti, J., Balaña-Fouce, Rafael, and Martínez Valladares, María

Abstract

Canine leishmaniasis is an important vector-borne protozoan disease in dogs that is re-sponsible for serious deterioration in their health. In the Iberian Peninsula, as in most countriessurrounding the Mediterranean Sea, canine leishmaniasis is caused byLeishmania infantum(zy-modeme MON-1), a digenetic trypanosomatid that harbors in the parasitophorous vacuoles of hostmacrophages, causing severe lesions that can lead to death if the animals do not receive adequatetreatment. Canine leishmaniasis is highly prevalent in Spain, especially in the Mediterranean coastalregions (Levante, Andalusia and the Balearic Islands), where the population of domestic dogs is veryhigh. However, the presence of this disease has been spreading to other rural and sparsely populatedlatitudes, and cases of leishmaniasis have been reported for years in wildlife in northwestern Spain.This work describes for the first time the presence of wolves that tested positive for leishmaniasis inthe vicinity of the Sierra de la Culebra (Zamora province, northwestern Spain), a protected sanctuaryof this canid species, using PCR amplification ofL. infantumDNA from different non-invasive samplessuch as buccal mucosa and those from both ears and hair. In addition to live animals (21), samplesfrom carcasses of mainly roadkill animals (18) were also included and analyzed using the sametechnique, obtaining a positivity rate of 18 of the 39 wolves sampled (46.1%) regardless of their origin.

Published
2023

18. Further investigations of nitroheterocyclic compounds as potential antikinetoplastid drug candidates

Author

Ministerio de Economía y Competitividad (España), Martínez Valladares, María [0000-0002-3723-1895], García-Estrada, C., Pérez-Pertejo, Y., Domínguez-Asenjo, B., Holanda, V.N., Murugesan, S., Martínez Valladares, María, Balaña-Fouce, Rafael, Reguera, R.M., Ministerio de Economía y Competitividad (España), Martínez Valladares, María [0000-0002-3723-1895], García-Estrada, C., Pérez-Pertejo, Y., Domínguez-Asenjo, B., Holanda, V.N., Murugesan, S., Martínez Valladares, María, Balaña-Fouce, Rafael, and Reguera, R.M.

Abstract

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

Published
2023

19. Specific levels of IgA as biomarker for gastrointestinal nematode infections under natural conditions in different sheep breeds

Author

Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Cambra-Pelletjà, María [0000-0002-8898-992X], Castilla Gómez de Agüero, V., Valderas García, E., Cambra Pellejà, M., González del Palacio, L., Balaña Fouce, R., Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Cambra-Pelletjà, María [0000-0002-8898-992X], Castilla Gómez de Agüero, V., Valderas García, E., Cambra Pellejà, M., González del Palacio, L., Balaña Fouce, R., and Martínez Valladares, María

Published
2023

20. Albendazole resistance in Fasciola hepatica: surveillance in different areas of Spain and Argentine

Author

Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Álvarez, L., Lirón, J.P., Canton, C., Castilla Gómez de Agüero, V., Valderas García E., Larroza, M., Soler, P., Lanusse, C., Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Álvarez, L., Lirón, J.P., Canton, C., Castilla Gómez de Agüero, V., Valderas García E., Larroza, M., Soler, P., Lanusse, C., and Martínez Valladares, María

Published
2023

21. Screening of drug collections on Caenorhabditis elegans using the motility-based system wMicrotracker

Author

Valderas García, Elora [0000-0002-9970-896X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Martínez Valladares, María [0000-0002-3723-1895], Valderas García, E., Ruiz Somacarrera, M., González del Palacio, L., Castilla Gómez de Agüero, V., Martínez Valladares, María, Balaña Fouce, R., Galli, G., Valderas García, Elora [0000-0002-9970-896X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Martínez Valladares, María [0000-0002-3723-1895], Valderas García, E., Ruiz Somacarrera, M., González del Palacio, L., Castilla Gómez de Agüero, V., Martínez Valladares, María, Balaña Fouce, R., and Galli, G.

Published
2023

22. Screening of newly synthetized benzimidazole compounds with fasciolicidal properties

Author

Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas-García, E., Díaz García, J., Castilla Gómez de Agüero, V., González del Palacio, L., Ruiz Somacarrera, M., Del Olmo, E., Balaña Fouce, R., Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora [0000-0002-9970-896X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas-García, E., Díaz García, J., Castilla Gómez de Agüero, V., González del Palacio, L., Ruiz Somacarrera, M., Del Olmo, E., Balaña Fouce, R., and Martínez Valladares, María

Published
2023

23. Efficacy of injectable eprinomectin (Eprecis® 20 mg/mL) for the treatment of larval Oestrus ovis infestation in naturally infected sheep

Author

Martínez Valladares, María [0000-0002-3723-1895], Sotiraki, S., Martínez Valladares, María, Baka, O., Ligda, P., González, L., Stefanakis, A., Pobel, T., Achard, D., Caruso-Vares, A., Martínez Valladares, María [0000-0002-3723-1895], Sotiraki, S., Martínez Valladares, María, Baka, O., Ligda, P., González, L., Stefanakis, A., Pobel, T., Achard, D., and Caruso-Vares, A.

Published
2023

24. Monitoring of ivermectin residues in bovine and pork tissues

Author

Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Martínez Valladares, María [0000-0002-3723-1895], Álvarez, L., Lirón, J.P., Canton, C., Castilla Gómez de Agüero, V., Valderas García, E., Larroza, M., Soler, P., Lanusse, C., Martínez Valladares, María, Cantón, L., Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Martínez Valladares, María [0000-0002-3723-1895], Álvarez, L., Lirón, J.P., Canton, C., Castilla Gómez de Agüero, V., Valderas García, E., Larroza, M., Soler, P., Lanusse, C., Martínez Valladares, María, and Cantón, L.

Published
2023

27. 100 Questions in Livestock Helminthology Research

Author

Morgan, Eric R., Aziz, Nor-Azlina A., Blanchard, Alexandra, Charlier, Johannes, Charvet, Claude, Claerebout, Edwin, Geldhof, Peter, Greer, Andrew W., Hertzberg, Hubertus, Hodgkinson, Jane, Höglund, Johan, Hoste, Hervé, Kaplan, Ray M., Martínez-Valladares, María, Mitchell, Siân, Ploeger, Harm W., Rinaldi, Laura, von Samson-Himmelstjerna, Georg, Sotiraki, Smaragda, Schnyder, Manuela, Skuce, Philip, Bartley, David, Kenyon, Fiona, Thamsborg, Stig M., Vineer, Hannah Rose, de Waal, Theo, Williams, Andrew R., van Wyk, Jan A., and Vercruysse, Jozef

Published
2019
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28. Treatment and Healing of Leishmaniasis in a Wolf in Semi-Captivity Regime from an Educational Center of Zamora Province (Spain).

Author

Merino-Goyenechea, Javier, Palacios-Alberti, Jesús, Yanes-Martínez, Tomás, Martínez-Valladares, María, and Balaña-Fouce, Rafael

Subjects
LEISHMANIASIS, HEALING, WOLVES, VECTOR-borne diseases, LEISHMANIA infantum, SERUM, WOUND healing
Abstract

Simple Summary: Leishmania infantum is a single-celled trypanosomatid responsible for canine leishmaniasis, a serious disease that causes a generalized inflammatory reaction including, among others, lymphadenopathy, hepatomegaly, and splenomegaly in dogs. Increasing information on leishmaniasis in wildlife shows that many mammalian species can act as reservoirs, being a serious threat to domestic dog populations and public health. Our case describes a female wolf suffering from lameness due to an ulcerative wound on the right forepaw, with hyper-gammaglobulinemia, high serum GPT levels, and positive ELISA tests for antibodies to Leishmania infantum antigens as confirmed by PCR. The wolf responded positively to conventional treatment of leishmaniasis, and all altered parameters were restored. Leishmaniasis in wild canids is a vector-borne disease caused in Europe by the protozoan parasite Leishmania infantum. To date, there is limited information on clinical signs and laboratory abnormalities in wolves due to leishmaniasis. The current clinical case report described a female Iberian wolf (Canis lupus signatus) housed in semi-captivity conditions at the Centro del Lobo Ibérico "Félix Rodríguez de la Fuente", in Robledo de Sanabria, Zamora (Spain), with an interdigital ulcerous wound at the right forepaw, hyper-gammaglobulinemia, and abnormal liver blood parameters. Definitive serodiagnosis of leishmaniasis was established using antileishmanial serum antibodies and PCR analysis of different biological samples. A gold-standard anti-L. infantum treatment protocol consisting in subcutaneous meglumine antimoniate and oral allopurinol combination was installed. However, the presence of pain at the site of injection due to meglumine antimoniate administration forced its substitution by oral miltefosine. A progressive reduction of the levels of anti-L. infantum serum antibodies and the concentrations of gamma-globulin fraction was detected after antileishmanial treatment as well as a decline of liver GPT. To our knowledge, this is the first case of leishmaniasis diagnosed in a wolf housed in semi-captivity conditions, with the condition subsequently treated and successfully cured. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Antileishmanial Effect of 1,5- and 1,8-Substituted Fused Naphthyridines.

Author

Melcón-Fernandez, Estela, Martín-Encinas, Endika, Palacios, Francisco, Galli, Gulio, Reguera, Rosa M., Martínez-Valladares, María, Balaña-Fouce, Rafael, Alonso, Concepción, and Pérez-Pertejo, Yolanda

Subjects
NAPHTHYRIDINES, NEGLECTED diseases, ORAL drug administration, LEISHMANIA infantum, LEISHMANIASIS
Abstract

In the absence of a vaccine, there is a need to find new drugs for the treatment of neglected tropical diseases, such as leishmaniasis, that can overcome the many drawbacks of those currently used. These disadvantages include cost, the need to maintain a cold chain, the route of administration, the associated adverse effects and the generation of resistance. In this work we have evaluated the antileishmanial effect of 1,5- and 1,8-substituted fused naphthyridines through in vitro and ex vivo assays, using genetically modified axenic and intramacrophagic Leishmania infantum amastigotes. The toxicity of these compounds has been tested in the mammalian host cell using murine splenic macrophages, as well as in murine intestinal organoids (miniguts) in order to assess their potential for oral administration. The 1,8- derivatives showed greater leishmanicidal activity and the presence of a nitrogen atom in the fused ring to the naphthyridine was important to increase the activity of both types of molecules. The aromatization of the pyridine ring also had marked differences in the activity of the compounds. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Secretory IgA as Biomarker for Gastrointestinal Nematodes Natural Infection in Different Breed Sheep

Author

Castilla Gómez de Agüero, Verónica, Valderas-García, Elora, González del Palacio, Laura, Giráldez, F. Javier, Balaña-Fouce, Rafael, and Martínez-Valladares, María

Abstract

Specific IgA antibody has been shown to play an important role in resistance to gastrointestinal nematode (GIN) infections in sheep, particularly in Teladorsagia circumcincta parasitosis. In some breeds, negative associations have been shown between IgA levels and worm burden in experimentally infected sheep. In the present study, we have studied the relationship between IgA levels in naturally infected sheep (582 ewes in total; 193 younger than one year old and 389 older than one year old) and fecal egg count (FEC) in the Assaf, Castellana, and Churra breeds. ELISA assays were performed to measure IgA levels against the somatic antigen of T. circumcincta third larval stage (L3) and a 203-amino-acid fragment of the protein disulfide isomerase from the same GIN species. A multilevel random intercept model was developed to predict the infection risk according to age or breed. Spearman’s correlation rank was used for statistical analysis. The prediction model showed that breed was not an influential factor in this study, although the Assaf breed could be considered slightly more susceptible than the others. In addition, age affected the infection risk, with the young ewes more susceptible to infection than the adult groups, except for the Castellana breed, whose risk of infection was similar at all ages. The most significant positive association was found between FEC and IgA measured in the nasal secretions of young ewes using both antigens (Rho = 0.5; p = 0.00); the correlation of FEC with IgA in serum was moderately significant (Rho = 0.306; p = 0.00). Comparing both antigens, the protein disulfide isomerase antigen was less reactive than the somatic antigen from L3. In conclusion, under natural conditions, specific IgA against GIN was positively associated with FEC in sheep, with nasal secretions from young animals being the sample where this association is stronger, which, therefore, could be used as a marker of infection in further studies.

Published
2023

33. Resistencia al albendazol en un rebaño de ganado ovino infectado por Fasciola hepatica y alternativas de tratamiento.

Author

Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], González del Palacio, Laura, Castilla Gómez de Agüero, Verónica, Valderas García, Elora, Cambra Pelletjá, María, Balaña-Fouce, Rafael, Álvarez, L. I., Martínez Valladares, María, Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], González del Palacio, Laura, Castilla Gómez de Agüero, Verónica, Valderas García, Elora, Cambra Pelletjá, María, Balaña-Fouce, Rafael, Álvarez, L. I., and Martínez Valladares, María

Published
2022

34. Increasing importance of anthelmintic resistance in European livestock: creation and meta-analysis of an open database

Author

Martínez Valladares, María [0000-0002-3723-1895], Rose Vineer, H., Morgan, E.R., Hertzberg, H., Bartley, D.J., Bosco, A., Charlier, J., Chartier, C., Claerebout, E., De Waal, T., Hendrickx, G., Hinney, B., Höglund, J., Jezek, J., Kasny, M., Keane, O.M., Martínez Valladares, María, Letra Mateus, T., Mclntyre, J., Mickiewicz, M., Muñoz, A.M., Phythian, C.J., Ploeger, H.W., Vergles, A., Skuce, P.J., Simin, S., Sotiraki, S., Spinu, M., Stuen, S., Thamsborg, S.M., Vadlejch, J., Varady, M., Von Samson-Himmelstjerna, G., Rinaldi, L., Martínez Valladares, María [0000-0002-3723-1895], Rose Vineer, H., Morgan, E.R., Hertzberg, H., Bartley, D.J., Bosco, A., Charlier, J., Chartier, C., Claerebout, E., De Waal, T., Hendrickx, G., Hinney, B., Höglund, J., Jezek, J., Kasny, M., Keane, O.M., Martínez Valladares, María, Letra Mateus, T., Mclntyre, J., Mickiewicz, M., Muñoz, A.M., Phythian, C.J., Ploeger, H.W., Vergles, A., Skuce, P.J., Simin, S., Sotiraki, S., Spinu, M., Stuen, S., Thamsborg, S.M., Vadlejch, J., Varady, M., Von Samson-Himmelstjerna, G., and Rinaldi, L.

Published
2022

35. Determinación de los niveles de IgA frente nematodos gastrointestinales como marcador de resistencia a la infección en el ganado ovino

Author

Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Cambra-Pelletjà, María [0000-0002-8898-992X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica, Valderas García, Elora, Cambra Pelletjá, María, González del Palacio, Laura, Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Cambra-Pelletjà, María [0000-0002-8898-992X], González del Palacio, Laura [0000-0002-6396-120X], Castilla Gómez de Agüero, Verónica, Valderas García, Elora, Cambra Pelletjá, María, González del Palacio, Laura, and Martínez Valladares, María

Published
2022

36. Molecular docking analysis of Strongyloides stercoralis beta-tubulin gene and its interaction with benzimidazoles

Author

Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], Cambra Pelletjá, María, Nogueira Holanda, V., Díaz Fernández, N., Suárez Rodríguez, D., Escola, V., Gandasegui, Javier, Messa Junior, A., Balaña-Fouce, Rafael, Muñoz, J., Martínez Valladares, María, Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], Cambra Pelletjá, María, Nogueira Holanda, V., Díaz Fernández, N., Suárez Rodríguez, D., Escola, V., Gandasegui, Javier, Messa Junior, A., Balaña-Fouce, Rafael, Muñoz, J., and Martínez Valladares, María

Published
2022

38. Present and future options of parasite control

Author

Martínez Valladares, María [0000-0002-3723-1895], Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], and Martínez Valladares, María

Published
2022

39. Anthelmintic resistance in ruminants: challenges and solutions

Author

European Cooperation in Science and Technology, Danish Council for Independent Research, Scottish Government's Rural and Environment Science and Analytical Services, UK Research and Innovation, Martínez Valladares, María [0000-0002-3723-1895], Charlier, J., Bartley, D.J., Sotiraki, S., Martínez Valladares, María, Claerebout, E., Von Sanson-Himmelstjerna, G., Thamsborg, S.M., Hoste, H., Morgan, E.R., Rinaldi, L., European Cooperation in Science and Technology, Danish Council for Independent Research, Scottish Government's Rural and Environment Science and Analytical Services, UK Research and Innovation, Martínez Valladares, María [0000-0002-3723-1895], Charlier, J., Bartley, D.J., Sotiraki, S., Martínez Valladares, María, Claerebout, E., Von Sanson-Himmelstjerna, G., Thamsborg, S.M., Hoste, H., Morgan, E.R., and Rinaldi, L.

Abstract

Anthelmintic resistance (AR) is a growing concern for effective parasite control in farmed ruminants globally. Combatting AR will require intensified and integrated research efforts in the development of innovative diagnostic tests to detect helminth infections and AR, sustainable anthelmintic treatment strategies and the development of complementary control approaches such as vaccination and plant-based control. It will also require a better understanding of socio-economic drivers of anthelmintic treatment decisions, in order to support a behavioural shift and develop targeted communication strategies that promote the uptake of evidence-based sustainable solutions. Here, we review the state-of-the-art in these different fields of research activity related to AR in helminths of livestock ruminants in Europe and beyond. We conclude that in the advent of new challenges and solutions emerging from continuing spread of AR and intensified research efforts, respectively, there is a strong need for transnational multi-actor initiatives. These should involve all key stakeholders to develop indicators of infection and sustainable control, set targets and promote good practices to achieve them.

Published
2022

40. A novel benzimidazole derivative shows in vivo anthelmintic activity against in gerbils and sheep

Author

Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora, Escala, N., De La Vega, J., Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, González Palacios, L., Vallejo, R., Del Olmo, E., Balaña-Fouce, Rafael, Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora, Escala, N., De La Vega, J., Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, González Palacios, L., Vallejo, R., Del Olmo, E., Balaña-Fouce, Rafael, and Martínez Valladares, María

Published
2022

41. Changes in the microbiome composition in Churra sheep with a resistant phenotype to infection

Author

Andrés, Sonia [0000-0001-5255-1582], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica, Esteban-Blanco, C., Argüello, H., Valderas García, Elora, Andrés, Sonia, Arranz, J.J., Gutiérrez-Gil, Beatriz, Martínez Valladares, María, Andrés, Sonia [0000-0001-5255-1582], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Valderas García, Elora [0000-0002-9970-896X], Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica, Esteban-Blanco, C., Argüello, H., Valderas García, Elora, Andrés, Sonia, Arranz, J.J., Gutiérrez-Gil, Beatriz, and Martínez Valladares, María

Published
2022

42. An adaptive phase II/III safety and efficacy randomized controlled trial of single day or three-day fixed-dose albendazole-ivermectin co-formulation versus albendazole for the treatment of Trichuris trichiura and other STH infections. ALIVE trial protocol

Author

Martínez Valladares, María [0000-0002-3723-1895], Krolewiecki, A., Enbiale, W., Gandasegui, Javier, van Lieshout, L., Kepha, S., Messa Junior, A., Bengtson, M., Gelaye, W., Escola, V., Martínez Valladares, María, Cambra Pelletjá, María, Algorta, J., Martí-Soler, H., Fleitas, P., Ballester, M.R., Doyle, S.R., Williams, N.A., Legarda, A., Mandomando, I., Mwandawiro, C., Muñoz, J., Martínez Valladares, María [0000-0002-3723-1895], Krolewiecki, A., Enbiale, W., Gandasegui, Javier, van Lieshout, L., Kepha, S., Messa Junior, A., Bengtson, M., Gelaye, W., Escola, V., Martínez Valladares, María, Cambra Pelletjá, María, Algorta, J., Martí-Soler, H., Fleitas, P., Ballester, M.R., Doyle, S.R., Williams, N.A., Legarda, A., Mandomando, I., Mwandawiro, C., and Muñoz, J.

Abstract

Background: Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against Trichuris trichiura and a predictable low efficacy against Strongyloides stercoralis. Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH. Methods: An adaptive phase II/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126 T. trichiura-infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with T. trichiura, hookworm and S. stercoralis will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance. Conclusions: This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of prov

Published
2022

43. In vitro evaluation of novel benzimidazole derivatives against Fasciola hepática

Author

Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], González del Palacio, Laura, Valderas García, Elora, Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, Del Olmo, E., Balaña-Fouce, Rafael, Martínez Valladares, María, Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Cambra-Pelletjà, María [0000-0002-8898-992X], Martínez Valladares, María [0000-0002-3723-1895], González del Palacio, Laura, Valderas García, Elora, Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, Del Olmo, E., Balaña-Fouce, Rafael, and Martínez Valladares, María

Published
2022

44. Advances in diagnosis of gastrointestinal nematodes in livestock and companion animals

Author

European Cooperation in Science and Technology, Livestock Helminth Research Alliance, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Rinaldi, L., Krücken, J., Martínez Valladares, María, Pepe, P., Maurelli, M.P., De Queiroz, C., Castilla Gómez de Agüero, Verónica, Wang, T., Cringoli, G., Charlier, J., Gilleard, J.S., Von Samson Himmelstjerna, G., European Cooperation in Science and Technology, Livestock Helminth Research Alliance, Martínez Valladares, María [0000-0002-3723-1895], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Rinaldi, L., Krücken, J., Martínez Valladares, María, Pepe, P., Maurelli, M.P., De Queiroz, C., Castilla Gómez de Agüero, Verónica, Wang, T., Cringoli, G., Charlier, J., Gilleard, J.S., and Von Samson Himmelstjerna, G.

Abstract

Diagnosis of gastrointestinal nematodes in livestock and companion animals has been neglected for years and there has been an historical underinvestment in the develop- ment and improvement of diagnostic tools, undermining the undoubted utility of surveillance and control programmes. However, a new impetus by the scientific com- munity and the quickening pace of technological innovations, are promoting a renais- sance of interest in developing diagnostic capacity for nematode infections in veterinary parasitology. A cross-cutting priority for diagnostic tools is the development of pen-side tests and associated decision support tools that rapidly inform on the levels of infection and morbidity. This includes development of scalable, parasite detection using artificial intelligence for automated counting of parasitic elements and research towards esta- blishing biomarkers using innovative molecular and proteomic methods. The aim of this review is to assess the state-of-the-art in the diagnosis of helminth infections in livestock and companion animals and presents the current advances of diagnostic methods for intestinal parasites harnessing (i) automated methods for copromicroscopy based on artificial intelligence, (ii) immunodiagnosis, and (iii) molecular- and proteome-based approaches. Regardless of the method used, multiple factors need to be considered before diagnostics test results can be interpreted in terms of control decisions. Guidelines on how to apply diagnostics and how to interpret test results in different animal species are increasingly requested and some were recently made available in veterinary parasitology for the different domestic species.

Published
2022

45. Presencia de Leishmania infantum en distintas muestras biológicas de lobos ibéricos (Canis lupus signatus) de la provincia de Zamora

Author

Martínez Valladares, María [0000-0002-3723-1895], Merino Goyenechea, L.J., Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, Valderas García, Elora, Balaña-Fouce, Rafael, Martínez Valladares, María, Martínez Valladares, María [0000-0002-3723-1895], Merino Goyenechea, L.J., Castilla Gómez de Agüero, Verónica, Cambra Pelletjá, María, Valderas García, Elora, Balaña-Fouce, Rafael, and Martínez Valladares, María

Published
2022

46. Single-nucleotide polymorphisms in the beta-tubulin gene and its relationship with treatment response to albendazole in human soil-transmitted helminths in southern Mozambique

Author

British Society for Antimicrobial Chemotherapy, Fundación Mundo Sano, Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Agencia Española de Cooperación Internacional para el Desarrollo, Governo de Moçambique, Junta de Castilla y León, European Commission, Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Ministerio de Economía, Industria y Competitividad (España), Martínez Valladares, María [0000-0002-3723-1895], Cambra-Pelletjà, María [0000-0002-8898-992X], Grau-Pujol, B., Gandasegui, Javier, Escola, V., Martí-Soler, H., Cambra Pelletjá, María, Demontis, M., Brienen, E.A.T., Jamine, J.C., Muchisse, O., Cossa, A., Sacoor, C., Cano, J., Van Lieshout, L., Martínez Valladares, María, Muñoz, J., British Society for Antimicrobial Chemotherapy, Fundación Mundo Sano, Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Agencia Española de Cooperación Internacional para el Desarrollo, Governo de Moçambique, Junta de Castilla y León, European Commission, Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Ministerio de Economía, Industria y Competitividad (España), Martínez Valladares, María [0000-0002-3723-1895], Cambra-Pelletjà, María [0000-0002-8898-992X], Grau-Pujol, B., Gandasegui, Javier, Escola, V., Martí-Soler, H., Cambra Pelletjá, María, Demontis, M., Brienen, E.A.T., Jamine, J.C., Muchisse, O., Cossa, A., Sacoor, C., Cano, J., Van Lieshout, L., Martínez Valladares, María, and Muñoz, J.

Abstract

Soil-transmitted helminth (STH) cornerstone control strategy is mass drug administration (MDA) with benzimidazoles. However, MDA might contribute to selection pressure for anthelmintic resistance, as occurred in livestock. The aim of this study is to evaluate the treatment response to albendazole and the relationship with the presence of putative benzimidazole resistance single-nucleotide polymorphisms (SNPs) in the b-tubulin gene of STH in Southern Mozambique. After screening 819 participants, we conducted a cohort study with 184 participants infected with STH in Manhic¸ a district, Southern Mozambique. A pretreatment and a posttreatment stool samples were collected and the STH infection was identified by duplicate Kato-Katz and quantitative polymerase chain reaction (qPCR). Cure rate and egg reduction rates were calculated. Putative benzimidazole resistance SNPs (F167Y, F200T, and E198A) in Trichuris trichiura and Necator americanus were assessed by pyrosequencing. Cure rates by duplicate Kato-Katz and by qPCR were 95.8% and 93.6% for Ascaris lumbricoides, 28% and 7.8% for T. trichiura, and 88.9% and 56.7% for N. americanus. Egg reduction rate by duplicate Kato-Katz was 85.4% for A. lumbricoides, 34.9% for T. trichiura, and 40.5% for N. americanus. Putative benzimidazole resistance SNPs in the b-tubulin gene were detected in T. trichiura (23%) and N. americanus (21%) infected participants at pretreatment. No statistical difference was observed between pretreatment and posttreatment frequencies for none of the SNPs. Although treatment response to albendazole was low, particularly in T. trichiura, the putative benzimidazole resistance SNPs were not higher after treatment in the population studied. New insights are needed for a better understanding and monitoring of human anthelmintic resistance.

Published
2022

47. Benzimidazole and aminoalcohol derivatives show in vitro anthelmintic activity against Trichuris muris and Heligmosomoides polygyrus

Author

Ministerio de Economía y Competitividad (España), Junta de Castilla y León, European Commission, Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora, Häberli, C., Álvarez-Bardón, M., Escala, N., Castilla Gómez de Agüero, Verónica, Vega, J. De La, Olmo, E., Balaña-Fouce, Rafael, Keiser, J., Martínez Valladares, María, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, European Commission, Valderas García, Elora [0000-0002-9970-896X], Castilla Gómez de Agüero, Verónica [0000-0002-6797-0170], Martínez Valladares, María [0000-0002-3723-1895], Valderas García, Elora, Häberli, C., Álvarez-Bardón, M., Escala, N., Castilla Gómez de Agüero, Verónica, Vega, J. De La, Olmo, E., Balaña-Fouce, Rafael, Keiser, J., and Martínez Valladares, María

Abstract

Background: Infections by gastrointestinal nematodes cause significant economic losses and disease in both humans and animals worldwide. The discovery of novel anthelmintic drugs is crucial for maintaining control of these parasitic infections. Methods: For this purpose, the aim of the present study was to evaluate the potential anthelmintic activity of three series of compounds against the gastrointestinal nematodes Trichuris muris and Heligmosomoides polygyrus in vitro. The compounds tested were derivatives of benzimidazole, lipidic aminoalcohols and diamines. A primary screening was performed to select those compounds with an ability to inhibit T. muris L1 motility by > 90% at a single concentration of 100 µM; then, their respective IC50 values were calculated. Those compounds with IC50 < 10 µM were also tested against the adult stage of T. muris and H. polygyrus at a single concentration of 10 µM. Results: Of the 41 initial compounds screened, only compounds AO14, BZ6 and BZ12 had IC50 values < 10 µM on T. muris L1 assay, showing IC50 values of 3.30, 8.89 and 4.17 µM, respectively. However, only two of them displayed activity against the adult stage of the parasites: BZ12 killed 81% of adults of T. muris (IC50 of 8.1 µM) and 53% of H. polygyrus while BZ6 killed 100% of H. polygyrus adults (IC50 of 5.3 µM) but only 17% of T. muris. Conclusions: BZ6 and BZ12 could be considered as a starting point for the synthesis of further structurally related compounds. Graphical

Published
2022

50. Antileishmanial Effect of 1,5- and 1,8-Substituted Fused Naphthyridines

Author

Química orgánica I, Kimika organikoa I, Melcón-Fernandez, Estela, Martín Encinas, Endika, Palacios Gambra, Francisco Javier, Galli, Gulio, Reguera, Rosa M., Martínez Valladares, María, Balaña Fouce, Rafael, Alonso Pérez, Concepción Estibaliz, Pérez Pertejo, Yolanda, Química orgánica I, Kimika organikoa I, Melcón-Fernandez, Estela, Martín Encinas, Endika, Palacios Gambra, Francisco Javier, Galli, Gulio, Reguera, Rosa M., Martínez Valladares, María, Balaña Fouce, Rafael, Alonso Pérez, Concepción Estibaliz, and Pérez Pertejo, Yolanda

Abstract

In the absence of a vaccine, there is a need to find new drugs for the treatment of neglected tropical diseases, such as leishmaniasis, that can overcome the many drawbacks of those currently used. These disadvantages include cost, the need to maintain a cold chain, the route of administration, the associated adverse effects and the generation of resistance. In this work we have evaluated the antileishmanial effect of 1,5- and 1,8-substituted fused naphthyridines through in vitro and ex vivo assays, using genetically modified axenic and intramacrophagic Leishmania infantum amastigotes. The toxicity of these compounds has been tested in the mammalian host cell using murine splenic macrophages, as well as in murine intestinal organoids (miniguts) in order to assess their potential for oral administration. The 1,8- derivatives showed greater leishmanicidal activity and the presence of a nitrogen atom in the fused ring to the naphthyridine was important to increase the activity of both types of molecules. The aromatization of the pyridine ring also had marked differences in the activity of the compounds.

Published
2023

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