International Journal for Parasitology: Drugs and Drug Resistance最新文献

{"title":"Treating cryptosporidiosis: A review on drug discovery strategies","authors":"Anne-Charlotte Lenière,&nbsp;Alexis Vlandas,&nbsp;Jérôme Follet","doi":"10.1016/j.ijpddr.2024.100542","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100542","url":null,"abstract":"<div><p>Despite several decades of research on therapeutics, cryptosporidiosis remains a major concern for human and animal health. Even though this field of research to assess antiparasitic drug activity is highly active and competitive, only one molecule is authorized to be used in humans. However, this molecule was not efficacious in immunocompromised people and the lack of animal therapeutics remains a cause of concern. Indeed, the therapeutic arsenal needs to be developed for both humans and animals. Our work aims to clarify research strategies that historically were diffuse and poorly directed. This paper reviews <em>in vitro</em> and <em>in vivo</em> methodologies to assess the activity of future therapeutic compounds by screening drug libraries or through drug repurposing. It focuses on High Throughput Screening methodologies (HTS) and discusses the lack of knowledge of target mechanisms. In addition, an overview of several specific metabolic pathways and enzymatic activities used as targets against <em>Cryptosporidium</em> is provided. These metabolic processes include glycolytic pathways, fatty acid production, kinase activities, tRNA elaboration, nucleotide synthesis, gene expression and mRNA maturation. As a conclusion, we highlight emerging future strategies for screening natural compounds and assessing drug resistance issues.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100542"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400023X/pdfft?md5=2c999fcac43efe99f255fbf85f5d4e5d&pid=1-s2.0-S221132072400023X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasmodium RNA triphosphatase validation as antimalarial target","authors":"Sonia Moliner-Cubel ,&nbsp;Noemi Bahamontes-Rosa ,&nbsp;Ane Rodriguez-Alejandre ,&nbsp;Pamela M. Nassau ,&nbsp;Argyrides Argyrou ,&nbsp;Anshu Bhardwaja ,&nbsp;Rachel C. Buxton ,&nbsp;David Calvo-Vicente ,&nbsp;Bernadette Mouzon ,&nbsp;William McDowell ,&nbsp;Alfonso Mendoza-Losana ,&nbsp;Maria G. Gomez-Lorenzo","doi":"10.1016/j.ijpddr.2024.100537","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100537","url":null,"abstract":"<div><p>Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery, identifies targets that are essential to establish or maintain the infection, tractable to be susceptible for inhibition, selective towards their human ortholog and amenable for large scale purification and high throughput screening. The work presented herein validates the <em>Plasmodium falciparum</em> mRNA 5’ triphosphatase (PfPRT1), the first enzymatic step to cap parasite nuclear mRNAs, as a candidate target for the development of new antimalarial compounds. mRNA capping is essential to maintain the integrity and stability of the messengers, allowing their translation. PfPRT1 has been identified as a member of the tunnel, metal dependent mRNA 5′ triphosphatase family which differs structurally and mechanistically from human metal independent mRNA 5′ triphosphatase. In the present study the essentiality of PfPRT1 was confirmed and molecular biology tools and methods for target purification, enzymatic assessment and target engagement were developed, with the goal of running a future high throughput screening to discover PfPRT1 inhibitors.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100537"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000186/pdfft?md5=e5fae98317910cf914e2a408c67afefe&pid=1-s2.0-S2211320724000186-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141163643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the antiplasmodial efficacy of synthetic 2,5-diphenyloxazole analogs of compounds naturally derived from Oxytropis lanata","authors":"Nanang R. Ariefta ,&nbsp;Koichi Narita ,&nbsp;Toshihiro Murata ,&nbsp;Yoshifumi Nishikawa","doi":"10.1016/j.ijpddr.2024.100540","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100540","url":null,"abstract":"<div><p>The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from <em>Oxytropis lanata</em>. Among 48 compounds, 14 potently inhibited the proliferation of <em>P. falciparum</em> strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC₅₀ values from 3.38 to 12.65 μM and 1.27–6.19 μM, respectively, and were toxic to human foreskin fibroblasts at 39.53–336.35 μM. Notably, Compounds <strong>31</strong> (2-(2′,3′-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and <strong>32</strong> (2-(2′,3′-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both <em>P. falciparum</em> strains (3D7/K1), with values &gt; 40.20/&gt;126.58 and &gt; 41.27/&gt; 59.06, respectively. In the IC₅₀ speed and stage-specific assays, Compounds <strong>31</strong> and <strong>32</strong> showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in <em>P. falciparum</em> 3D7, especially at concentrations 100 times their IC₅₀ values. In a 72-h in vitro exposure experiment at their respective IC₈₀ in <em>P. falciparum</em> 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound <strong>31</strong>-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on <em>P. yoelii</em> 17XNL-infected mice treated with Compounds <strong>31</strong> and <strong>32</strong> at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound <strong>31</strong>-treated: trial 1 12.7%, trial 2 15.8%; Compound <strong>32</strong>-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100540"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000216/pdfft?md5=1dfb0cb947387ac4f75ca834b9284ec5&pid=1-s2.0-S2211320724000216-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140650693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ouabain, ATPase inhibitor, potentially enhances the effect of polyhexamethylene biguanide on Acanthamoeba castellanii","authors":"Kuang-Yi Shih ,&nbsp;Yao-Tsung Chang ,&nbsp;Yu-Jen Wang ,&nbsp;Jian-Ming Huang","doi":"10.1016/j.ijpddr.2024.100550","DOIUrl":"10.1016/j.ijpddr.2024.100550","url":null,"abstract":"<div><p><em>Acanthamoeba</em>, a free-living amoeba, is commonly found in various natural environments, such as rivers and soil, as well as in public baths, swimming pools, and sewers. <em>Acanthamoeba</em> can cause severe illness such as granulomatous amoebic encephalitis and Acanthamoeba keratitis (AK) in humans. AK, the most recognized disease, can cause permanent visual impairment or blindness by affecting the cornea. AK commonly affects contact lens wearers who neglect proper cleaning habits. The symptoms of AK include epithelial and stromal destruction, corneal infiltrate, and intense ocular pain, occasionally necessitating surgical removal of the entire eyeball. Current AK treatment involves the hourly application of eye drops containing polyhexamethylene biocide (PHMB). However, studies have revealed their ineffectiveness against drug-resistant strains. <em>Acanthamoeba</em> can form cysts as a survival mechanism in adverse environments, though the exact mechanism remains unknown. Our experiments revealed that sodium P-type ATPase (ACA1_065450) is closely linked to encystation. In addition, various encystation buffers, such as MgCl₂ or NaCl, induced the expression of P-type ATPase. Furthermore, we used ouabain, an ATPase inhibitor, to inhibit the Na⁺/K⁺ ion pump, consequently decreasing the encystation rate of <em>Acanthamoeba</em>. Our primary objective is to develop an advanced treatment for AK. We anticipate that the combination of ouabain and PHMB may serve as an effective therapeutic approach against AK in the future.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100550"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000319/pdfft?md5=8a2b658d161227b10a8f26e5fc564a5a&pid=1-s2.0-S2211320724000319-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative tests of albendazole resistance in Caenorhabditis elegans beta-tubulin mutants","authors":"J.B. Collins ,&nbsp;Skyler A. Stone ,&nbsp;Emily J. Koury ,&nbsp;Anna G. Paredes ,&nbsp;Fiona Shao ,&nbsp;Crystal Lovato ,&nbsp;Michael Chen ,&nbsp;Richelle Shi ,&nbsp;Anwyn Y. Li ,&nbsp;Isa Candal ,&nbsp;Khadija Al Moutaa ,&nbsp;Nicolas D. Moya ,&nbsp;Erik C. Andersen","doi":"10.1016/j.ijpddr.2024.100556","DOIUrl":"10.1016/j.ijpddr.2024.100556","url":null,"abstract":"<div><p>Benzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in the <em>C. elegans</em> beta-tubulin gene <em>ben-1</em> and orthologs in parasitic species. However, variants in <em>ben-1</em> alone do not explain the differences in BZ responses across parasite populations. Here, we examined the roles of five <em>C. elegans</em> beta-tubulin genes (<em>tbb-1</em>, <em>mec-7</em>, <em>tbb-4</em>, <em>ben-1</em>, and <em>tbb-6</em>) in the BZ response as well as to determine if another beta-tubulin acts redundantly with <em>ben-1</em>. We generated <em>C. elegans</em> strains with a loss of each beta-tubulin gene, as well as strains with a loss of <em>tbb-1</em>, <em>mec-7</em>, <em>tbb-4</em>, or <em>tbb-6</em> in a genetic background that also lacks <em>ben-1</em>. We found that the loss of <em>ben-1</em> conferred the maximum level of resistance following exposure to a single concentration of albendazole, and the loss of a second beta-tubulin gene did not alter the level of resistance. However, additional traits other than larval development could be affected by the loss of additional beta-tubulins, and the roles of other beta-tubulin genes might be revealed at different albendazole concentrations. Therefore, further work is needed to fully define the possible roles of other beta-tubulin genes in the BZ response.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100556"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400037X/pdfft?md5=d41292adfb720dac255a79c591f51ed0&pid=1-s2.0-S221132072400037X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite","authors":"Haichuan Chen ,&nbsp;Dongqiang Wang ,&nbsp;Chenchen Wang ,&nbsp;Peng Jiang ,&nbsp;Mingxiao Liu ,&nbsp;Jigang Yin ,&nbsp;Yonglan Yu","doi":"10.1016/j.ijpddr.2024.100551","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100551","url":null,"abstract":"<div><p><em>Cryptosporidium parvum</em> is a waterborne and foodborne zoonotic protozoan parasite, a causative agent of moderate to severe diarrheal diseases in humans and animals. However, fully effective treatments are unavailable for medical and veterinary uses. There is a need to explore new drug targets for potential development of new therapeutics. Because <em>C. parvum</em> relies on anaerobic metabolism to produce ATP, fermentative enzymes in this parasite are attractive targets for exploration. In this study, we investigated the ethanol-fermentation in the parasite and characterized the basic biochemical features of a bacterial-type bifunctional aldehyde/alcohol dehydrogenase, namely CpAdhE. We also screened 3892 chemical entries from three libraries and identified 14 compounds showing &gt;50% inhibition on the enzyme activity of CpAdhE. Intriguingly, antifungal imidazoles and unsaturated fatty acids are the two major chemical groups among the top hits. We further characterized the inhibitory kinetics of selected imidazoles and unsaturated fatty acids on CpAdhE. These compounds displayed lower micromolar activities on CpAdhE (i.e., <em>IC</em>₅₀ values ranging from 0.88 to 11.02 μM for imidazoles and 8.93 to 35.33 μM for unsaturated fatty acids). Finally, we evaluated the in vitro anti-cryptosporidial efficacies and cytotoxicity of three imidazoles (i.e., tioconazole, miconazole and isoconazole). The three antifungal imidazoles exhibited lower micromolar efficacies against the growth of <em>C. parvum</em> in vitro (<em>EC</em>₅₀ values ranging from 4.85 to 10.41 μM and selectivity indices ranging from 5.19 to 10.95). The results provide a proof-of-concept data to support that imidazoles are worth being further investigated for potential development of anti-cryptosporidial therapeutics.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100551"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000320/pdfft?md5=a7fb67473afd2fb254b3759143180530&pid=1-s2.0-S2211320724000320-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141313418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Faecal egg count reduction tests and nemabiome analysis reveal high frequency of multi-resistant parasites on sheep farms in north-east Germany involving multiple strongyle parasite species","authors":"Jürgen Krücken ,&nbsp;Paula Ehnert ,&nbsp;Stefan Fiedler ,&nbsp;Fabian Horn ,&nbsp;Christina S. Helm ,&nbsp;Sabrina Ramünke ,&nbsp;Tanja Bartmann ,&nbsp;Alexandra Kahl ,&nbsp;Ann Neubert ,&nbsp;Wiebke Weiher ,&nbsp;Ricarda Daher ,&nbsp;Werner Terhalle ,&nbsp;Alexandra Klabunde-Negatsch ,&nbsp;Stephan Steuber ,&nbsp;Georg von Samson-Himmelstjerna","doi":"10.1016/j.ijpddr.2024.100547","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100547","url":null,"abstract":"<div><p>Anthelmintic resistance in sheep parasitic gastrointestinal nematodes is widespread and a severe health and economic issue but prevalence of resistance and involved parasite species are unknown in Germany. Here, the faecal egg count reduction test (FECRT) was performed on eight farms using fenbendazole, ivermectin and moxidectin and on four farms using only moxidectin. A questionnaire was used to obtain data on management practices to potentially identify risk factors for presence of resistance. All requirements of the recently revised WAAVP guideline for diagnosing anthelmintic resistance using the FECRT were applied. Nematode species composition in pre- and post-treatment samples was analysed with the nemabiome approach. Using the eggCounts statistic package, resistance against fenbendazole, ivermectin and moxidectin was found on 7/8, 8/8 and 8/12 farms, respectively. No formal risk factor analysis was conducted since resistance was present on most farms. Comparison with the bayescount R package results revealed substantial agreement between methods (Cohen's κ = 0.774). In contrast, interpretation of data comparing revised and original WAAVP guidelines resulted in moderate agreement (Cohen's κ = 0.444). The FECR for moxidectin was significantly higher than for ivermectin and fenbendazole. Nemabiome data identified 4 to 12 species in pre-treatment samples and treatments caused a small but significant decrease in species diversity (inverse Simpson index). Non-metric multidimensional scaling and k-means clustering were used to identify common patterns in pre- and post-treatment samples. However, post-treatment samples were scattered among the pre-treatment samples. Resistant parasite species differed between farms. In conclusion, the revised FECRT guideline allows robust detection of anthelmintic resistance. Resistance was widespread and involved multiple parasite species. Resistance against both drug classes on the same farm was common. Further studies including additional drugs (levamisole, monepantel, closantel) should combine sensitive FECRTs with nemabiome data to comprehensively characterise the anthelmintic susceptibility status of sheep nematodes in Germany.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100547"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000289/pdfft?md5=cefc4dcf8db5b07c8c628daa3b7cf9c9&pid=1-s2.0-S2211320724000289-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acaricide resistance status of livestock ticks from East and West Africa and in vivo efficacy of acaricides to control them","authors":"Alec Evans ,&nbsp;Maxime Madder ,&nbsp;Josephus Fourie ,&nbsp;Lénaïg Halos ,&nbsp;Bersissa Kumsa ,&nbsp;Elikira Kimbita ,&nbsp;Joseph Byaruhanga ,&nbsp;Frank Norbert Mwiine ,&nbsp;Dennis Muhanguzi ,&nbsp;Safiou Bienvenu Adehan ,&nbsp;Alassane Toure ,&nbsp;Jahashi Nzalawahe ,&nbsp;Fred Aboagye-Antwi ,&nbsp;Ndudim Isaac Ogo ,&nbsp;Leon Meyer ,&nbsp;Frans Jongejan ,&nbsp;Imad Bouzaidi Cheikhi ,&nbsp;Maggie Fisher ,&nbsp;Peter Holdsworth","doi":"10.1016/j.ijpddr.2024.100541","DOIUrl":"10.1016/j.ijpddr.2024.100541","url":null,"abstract":"<div><p>Through a collaborative effort across six Sub-Saharan African countries, using recognized international assessment techniques, 23 stocks of three tick species (<em>Rhipicephalus microplus, Rhipicephalus appendiculatus</em> and <em>Amblyomma variegatum)</em> of economic importance for rural small holder farming communities from East and West Africa were collected from cattle<em>,</em> and evaluated in <em>in vitro</em> larval packet tests (LPT). The results demonstrated medium to high resistance to chlorfenvinphos and amitraz across species. <em>Rhipicephalus microplus</em> demonstrated high level alpha-cypermethrin and cypermethrin resistance. Stocks of <em>A</em>. <em>variegatum</em> (West Africa) and <em>R</em>. <em>appendiculatus</em> (Uganda) demonstrated medium level ivermectin resistance.</p><p>The four least susceptible stocks (East and West African <em>R. microplus, A. variegatum</em> and <em>R. appendiculatus)</em> were taken into <em>in vivo</em> controlled cattle studies where fipronil was found effective against West and East African <em>R. microplus</em> isolates although persistent efficacy failed to reach 90%. Cymiazole and cypermethrin, and ivermectin based acaricides were partially effective against <em>R. microplus</em> without persistent efficacy. Flumethrin spray-on killed <em>A. variegatum</em> within 72 h for up to 10 days posttreatment, however product application was directly to tick attachment sites, which may be impractical under field conditions. A flumethrin pour-on formulation on goats provided persistent efficacy against <em>A. variegatum</em> for up to one-month. Therapeutic control was achieved against <em>R. appendiculatus</em> through weekly spraying cattle with flumethrin, amitraz or combined cymiazole and cypermethrin. A fipronil pour-on product offered four-week residual control against <em>R. appendiculatus</em> (with slow onset of action).</p><p>Few studies have assessed and directly compared acaricidal activity <em>in vitro</em> and <em>in vivo.</em> There was some discordance between efficacy indicated by LPT and <em>in vivo</em> results. This observation calls for more research into accurate and affordable assessment methods for acaricide resistance.</p><p>No single active or product was effective against all three tick species, emphasising the need for the development of alternative integrated tick management solutions.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100541"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000228/pdfft?md5=bda4ea540bd633855a1234e58b6eac46&pid=1-s2.0-S2211320724000228-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria","authors":"Zhuoru Jin ,&nbsp;Wei Pang ,&nbsp;Yan Zhao ,&nbsp;Hui Min ,&nbsp;Shijie Yao ,&nbsp;Zhifang Bian ,&nbsp;Yixin Wen ,&nbsp;Chuanyang Peng ,&nbsp;Yaming Cao ,&nbsp;Li Zheng","doi":"10.1016/j.ijpddr.2024.100539","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100539","url":null,"abstract":"<div><p>Infection with <em>Plasmodium falciparum</em> is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, <em>Plasmodium berghei</em> ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100539"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000204/pdfft?md5=01acea5ceacbc6298fc27269173191f8&pid=1-s2.0-S2211320724000204-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140551028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First case of macrocyclic lactone-resistant Dirofilaria immitis in Europe - Cause for concern","authors":"Donato Traversa ,&nbsp;Anastasia Diakou ,&nbsp;Mariasole Colombo ,&nbsp;Sohini Kumar ,&nbsp;Thavy Long ,&nbsp;Serafeim C. Chaintoutis ,&nbsp;Luigi Venco ,&nbsp;Gianluca Betti Miller ,&nbsp;Roger Prichard","doi":"10.1016/j.ijpddr.2024.100549","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100549","url":null,"abstract":"<div><p>Heartworm disease caused by the nematode <em>Dirofilaria immitis</em> is one of the most important parasitoses of dogs. The treatment of the infection is long, complicated, risky and expensive. Conversely, prevention is easy, safe, and effective and it is achieved by the administration of macrocyclic lactones (MLs). In recent years, <em>D. immitis</em> strains resistant to MLs have been described in Southern USA, raising concerns for possible emergence, or spreading in other areas of the world. The present study describes the first case of ML-resistant <em>D. immitis</em> in a dog in Europe. The dog arrived in Rome, Italy, from USA in 2023. Less than 6 months after its arrival in Italy, the dog tested positive for <em>D. immitis</em> circulating antigen and microfilariae, despite it having received monthly the ML milbemycin oxime (plus an isoxazoline) after arrival. The microfilariae suppression test suggested a resistant strain. Microfilariae DNA was examined by droplet digital PCR-based duplex assays targeting four marker positions at single nucleotide polymorphisms (SNP1, SNP2, SNP3, SNP7) which differentiate resistant from susceptible isolates. The genetic analysis showed that microfilariae had a ML-resistant genotype at SNP1 and SNP7 positions, compatible with a resistant strain. It is unlikely that the dog acquired the infection after its arrival in Europe, while it is biologically and epidemiologically plausible that the dog was already infected when imported from USA to Europe. The present report highlights the realistic risk of ML-resistant <em>D. immitis</em> strains being imported and possibly transmitted in Europe and other areas of the world. Monitoring dogs travelling from one area to another, especially if they originate from regions where ML-resistance is well-documented, is imperative. Scientists, practitioners, and pet owners should be aware of the risk and remain vigilant against ML-resistance, in order to monitor and reduce the spreading of resistant <em>D. immitis</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100549"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000307/pdfft?md5=3b7f04a849b1315ec7c73f8b0182faf0&pid=1-s2.0-S2211320724000307-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}