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

{"title":"In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii","authors":"Yanhua Qiu ,&nbsp;Bintao Zhai ,&nbsp;Yubin Bai ,&nbsp;Hongling Lin ,&nbsp;Lingyu Wu ,&nbsp;Wei Luo ,&nbsp;Mengyan Shi ,&nbsp;Shulin Chen ,&nbsp;Jiyu Zhang","doi":"10.1016/j.ijpddr.2024.100552","DOIUrl":"10.1016/j.ijpddr.2024.100552","url":null,"abstract":"<div><p><em>Toxoplasma gondii</em> (<em>T. gondii</em>) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-<em>T. gondii</em> activity of broxaldine (BRO) <em>in vitro</em> and <em>in vivo</em> and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 μg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of <em>T. gondii</em> and reduced the size and number of cysts <em>in vitro</em>. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of <em>T. gondii</em> was observed, including disintegration of <em>T. gondii</em>, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in <em>T. gondii</em> treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-<em>T. gondii</em> activity <em>in vitro</em> and <em>in vivo</em>; therefore, it has the potential to be used as a lead compound for anti-<em>T. gondii</em> treatment.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100552"},"PeriodicalIF":4.1,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000332/pdfft?md5=ea67480b952bf320577dc0399ea13b71&pid=1-s2.0-S2211320724000332-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579582","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":"Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice","authors":"Maria Cristina Ferreira de Sousa ,&nbsp;Dennis Imhof ,&nbsp;Kai Pascal Alexander Hänggeli ,&nbsp;Ryan Choi ,&nbsp;Matthew A. Hulverson ,&nbsp;Samuel L.M. Arnold ,&nbsp;Wesley C. Van Voorhis ,&nbsp;Erkang Fan ,&nbsp;Sánchez-Sánchez Roberto ,&nbsp;Luis M. Ortega-Mora ,&nbsp;Andrew Hemphill","doi":"10.1016/j.ijpddr.2024.100553","DOIUrl":"10.1016/j.ijpddr.2024.100553","url":null,"abstract":"<div><p><em>Toxoplasma gondii</em> and <em>Neospora caninum</em> are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) – and several members of this class have proven to be safe and highly active <em>in vitro</em> and <em>in vivo</em>. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited <em>in vitro</em> IC₅₀ values of 120 nM for <em>T. gondii</em> and 480 nM for <em>N. caninum</em> β-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 μM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 μM BKI-1708 <em>in vitro</em> induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (<em>Danio rerio</em>) embryo development during the first 96 h following egg hatching at concentrations up to 2 μM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 μM. <em>In vivo</em> efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9–13 of pregnancy in mice experimentally infected with <em>N. caninum</em> (NcSpain-7) tachyzoites or <em>T. gondii</em> (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100553"},"PeriodicalIF":4.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000344/pdfft?md5=05337ab18fdd00386b0462cc8f9ec858&pid=1-s2.0-S2211320724000344-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450433","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":"2024-06-06","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":"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":"2024-05-22","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":"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":"2024-05-21","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}

{"title":"Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin","authors":"Fisayo Olotu ,&nbsp;Mariscal Brice Tchatat Tali ,&nbsp;Curtis Chepsiror ,&nbsp;Olivier Sheik Amamuddy ,&nbsp;Fabrice Fekam Boyom ,&nbsp;Özlem Tastan Bishop","doi":"10.1016/j.ijpddr.2024.100548","DOIUrl":"10.1016/j.ijpddr.2024.100548","url":null,"abstract":"<div><p><em>Plasmodium falciparum</em> aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and <em>in vitro</em> antiplasmodial validation of <strong>Mitomycin</strong> (<strong>MMC</strong>) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. We combined multiple <em>in silico</em> structure-based discovery strategies that first helped identify functional and druggable sites that were preferentially targeted by the compound in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that <strong>MMC</strong> allosterically induced changes in the global structures of each protein. Likewise, prominent structural perturbations were caused by the compound across the functional domains of the proteins. More so, <strong>MMC</strong> induced systematic alterations in the binding of the catalytic nucleotide and amino acid substrates which culminated in the loss of key interactions with key active site residues and ultimate reduction in the nucleotide-binding affinities across all proteins, as deduced from the binding energy calculations. These altogether confirmed that <strong>MMC</strong> uniformly disrupted the structure of the target proteins and essential substrates. Further, <strong>MMC</strong> demonstrated <em>IC</em>_<em>50</em> &lt; 5 μM against the Dd2 and 3D7 strains of parasite making it a good starting point for malarial drug development. We believe that findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100548"},"PeriodicalIF":4.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000290/pdfft?md5=6251aac0cd410b41f7cb2265f47c4b80&pid=1-s2.0-S2211320724000290-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141134026","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":"Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box","authors":"Javier Chao-Pellicer ,&nbsp;Iñigo Arberas-Jiménez ,&nbsp;Ines Sifaoui ,&nbsp;José E. Piñero ,&nbsp;Jacob Lorenzo-Morales","doi":"10.1016/j.ijpddr.2024.100545","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100545","url":null,"abstract":"<div><p><em>Naegleria fowleri</em>, known as the brain-eating amoeba, is the pathogen that causes the primary amoebic meningoencephalitis (PAM), a severe neurodegenerative disease with a fatality rate exceeding 95%. Moreover, PAM cases commonly involved previous activities in warm freshwater bodies that allow amoebae-containing water through the nasal passages. Hence, awareness among healthcare professionals and the general public are the key to contribute to a higher and faster number of diagnoses worldwide. Current treatment options for PAM, such as amphotericin B and miltefosine, are limited by potential cytotoxic effects. In this context, the repurposing of existing compounds has emerged as a promising strategy. In this study, the evaluation of the COVID Box which contains 160 compounds demonstrated significant in vitro amoebicidal activity against two type strains of <em>N. fowleri</em>. From these compounds, terconazole, clemastine, ABT-239 and PD-144418 showed a higher selectivity against the parasite compared to the remaining products. In addition, programmed cell death assays were conducted with these four compounds, unveiling compatible metabolic events in treated amoebae. These compounds exhibited chromatin condensation and alterations in cell membrane permeability, indicating their potential to induce programmed cell death. Assessment of mitochondrial membrane potential disruption and a significant reduction in ATP production emphasized the impact of these compounds on the mitochondria, with the identification of increased ROS production underscoring their potential as effective treatment options. This study emphasizes the potential of the mentioned COVID Box compounds against <em>N. fowleri</em>, providing a path for enhanced PAM therapies.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100545"},"PeriodicalIF":4.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000265/pdfft?md5=349c6ecff988102637e77e002263689b&pid=1-s2.0-S2211320724000265-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878606","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":"2024-05-06","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":"Robenidine derivatives as potential antischistosomal drug candidates","authors":"Christian N. Lotz ,&nbsp;Alina Krollenbrock ,&nbsp;Lea Imhof ,&nbsp;Michael Riscoe ,&nbsp;Jennifer Keiser","doi":"10.1016/j.ijpddr.2024.100546","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100546","url":null,"abstract":"<div><p>Schistosomiasis caused by <em>Schistosoma</em> spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against <em>Plasmodium falciparum</em>, motivating further investigation into their efficacy against <em>Schistosoma mansoni,</em> due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult <em>Schistosoma mansoni</em> yielded 11 candidates with low EC₅₀ values for newly transformed schistosomula (1.12–4.63 μM) and adults (2.78–9.47 μM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of <em>Schistosoma mansoni</em>. The two compounds <em>2,2′-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride</em> (<strong>1</strong>) and <em>2,2′-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride</em> (<strong>19</strong>), were selected for an in vivo study in <em>Schistosoma mansoni</em>-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction &lt;20%). Thus, robenidine derivatives require further refinements to obtain higher antischistosomal specificity and in vivo activity.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100546"},"PeriodicalIF":4.0,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000277/pdfft?md5=07fc6d729d2617e9566802c376d81c41&pid=1-s2.0-S2211320724000277-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140906878","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":"2024-05-05","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}