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

{"title":"Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments","authors":"Katalin Toth ,&nbsp;Sevan Alwan ,&nbsp;Susan Khan ,&nbsp;Stanton F. McHardy ,&nbsp;Philip T. LoVerde ,&nbsp;Michael D. Cameron","doi":"10.1016/j.ijpddr.2023.01.003","DOIUrl":"10.1016/j.ijpddr.2023.01.003","url":null,"abstract":"<div><p>The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an <em>in vitro-in vivo</em> paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for <em>in vitro</em> schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with <em>in vitro</em> studies and explains the required human dose. <em>In silico</em> models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of <em>in vitro</em> efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill <em>S. mansoni, S. haematobium,</em> and <em>S. japonicum</em>, whereas OXA is only effective against <em>S. mansoni.</em> Second-generation OXA analogs should optimize both <em>in vitro</em> killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 65-73"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/a7/main.PMC9929523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9830092","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":"Effect of the pseudomonas metabolites HQNO on the Toxoplasma gondii RH strain in vitro and in vivo","authors":"Jiao Mo ,&nbsp;Hongfei Si ,&nbsp;Siyang Liu ,&nbsp;Qingyuan Zeng ,&nbsp;Minghao Cai ,&nbsp;Zhendi Liu ,&nbsp;Jiyu Zhang ,&nbsp;Jingjing Fang ,&nbsp;Jili Zhang","doi":"10.1016/j.ijpddr.2023.02.001","DOIUrl":"10.1016/j.ijpddr.2023.02.001","url":null,"abstract":"<div><p>Toxoplasmosis is a widespread disease in humans and animals. Currently, toxoplasmosis chemotherapy options are limited due to severe side effects. There is an urgent need to develop new drugs with better efficacy and few side effects. HQNO, a cytochrome <em>bc</em>1 and type II NADH inhibitor in eukaryotes and bacteria, possesses extensive bioactivity. In this study, the cytotoxicity of HQNO was evaluated in Vero cells. The <em>in vitro</em> effects of HQNO were determined by plaque assay and qPCR assay. To determine the <em>in vivo</em> effect of HQNO, pharmacokinetic experiments and <em>in vivo</em> infection assays were performed in mice. The changes in tachyzoites after HQNO exposure were examined by transmission electron microscopy (TEM), MitoTracker Red CMXRos staining, ROS detection and ATP detection. HQNO inhibited <em>T. gondii</em> invasion and proliferation with an EC₅₀ of 0.995 μM. Pharmacokinetic experiments showed that the C_max of HQNO (20 mg/kg·bw) was 3560 ± 1601 ng/mL (13.73 μM) in healthy BALB/c mouse plasma with no toxicity <em>in vivo</em>. Moreover, HQNO induced a significant decrease in the parasite burden load of <em>T. gondii</em> in mouse peritoneum. TEM revealed alterations in the mitochondria of <em>T. gondii</em>. Further assays verified that HQNO also decreased the mitochondrial membrane potential (ΔΨm) and ATP levels and enhanced the level of reactive oxygen species (ROS) in <em>T. gondii</em>. Hence, HQNO exerted <em>anti-T. gondii</em> activity, which may be related to the damage to the mitochondrial electron transport chain (ETC).</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 74-80"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/67/b8/main.PMC9929485.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9433828","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":"Poor adherence is a major barrier to the proper treatment of cutaneous leishmaniasis: A case-control field assessment in Iran","authors":"Mehdi Bamorovat ,&nbsp;Iraj Sharifi ,&nbsp;Setareh Agha Kuchak Afshari ,&nbsp;Ali Karamoozian ,&nbsp;Amirhossein Tahmouresi ,&nbsp;Amireh Heshmatkhah ,&nbsp;Ehsan Salarkia ,&nbsp;Ahmad Khosravi ,&nbsp;Maryam Hakimi Parizi ,&nbsp;Maryam Barghi","doi":"10.1016/j.ijpddr.2022.11.006","DOIUrl":"10.1016/j.ijpddr.2022.11.006","url":null,"abstract":"<div><p>Leishmaniasis is an overlooked, poverty-stricken, and complex disease with growing social and public health problems. In general, leishmaniasis is a curable disease; however, there is an expansion of unresponsive cases to treatment in cutaneous leishmaniasis (CL). One of the effective and ignored determinants in the treatment outcome of CL is poor treatment adherence (PTA). PTA is an overlooked and widespread phenomenon to proper <em>Leishmania</em> treatment. This study aimed to explore the effect of poor adherence in unresponsiveness to treatment in patients with anthroponotic CL (ACL) by comparing conventional statistical modalities and machine learning analyses in Iran. Overall, 190 cases consisting of 50 unresponsive patients (case group), and 140 responsive patients (control group) with ACL were randomly selected. The data collecting form that included 25 queries (Q) was recorded for each case and analyzed by R software and genetic algorithm (GA) approaches. Complex treatment regimens (Q11), cultural and lay views about the disease and therapy (Q8), life stress, hopelessness and negative feelings (Q22), adverse effects of treatment (Q13), and long duration of the lesion (Q12) were the most prevalent significant variables that inhibited effective treatment adherence by the two methods, in decreasing order of significance. In the inherent algorithm approach, similar to the statistical approach, the most significant feature was complex treatment regimens (Q11). Providing essential knowledge about ACL and treatment of patients with chronic diseases and patients with misconceptions about chemical drugs are important issues directly related to the disease's unresponsiveness. Furthermore, early detection of patients to prevent the long duration of the disease and the process of treatment, efforts to minimize side effects of treatment, induction of positive thinking, and giving hope to patients with stress and anxiety by medical staff, and family can help patients adhere to the treatment.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 21-27"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9445251","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":"Egg reappearance periods of anthelmintics against equine cyathostomins: The state of play revisited","authors":"Stephanie L. Macdonald ,&nbsp;Ghazanfar Abbas ,&nbsp;Abdul Ghafar ,&nbsp;Charles G. Gauci ,&nbsp;Jenni Bauquier ,&nbsp;Charles El-Hage ,&nbsp;Brett Tennent-Brown ,&nbsp;Edwina J.A. Wilkes ,&nbsp;Anne Beasley ,&nbsp;Caroline Jacobson ,&nbsp;Lucy Cudmore ,&nbsp;Peter Carrigan ,&nbsp;John Hurley ,&nbsp;Ian Beveridge ,&nbsp;Kristopher J. Hughes ,&nbsp;Martin K. Nielsen ,&nbsp;Abdul Jabbar","doi":"10.1016/j.ijpddr.2022.12.002","DOIUrl":"10.1016/j.ijpddr.2022.12.002","url":null,"abstract":"<div><p>Cyathostomins are the most common and highly prevalent parasites of horses worldwide. Historically, the control of cyathostomins has mainly relied on the routine use of anthelmintic products. Increasing reports on anthelmintic resistance (AR) in cyathostomins are concerning. A potential method proposed for detecting emerging AR in cyathostomins has been estimating the egg reappearance period (ERP). This paper reviews the data available for the ERP of cyathostomins against the three major classes of anthelmintics, macrocyclic lactones, tetrahydropyrimidines, and benzimidazoles. Published peer-reviewed original research articles were obtained from three databases (PubMed, CAB Direct and Web of Science) and were evaluated for their inclusion in a systematic review. Subsets of articles were then subjected to a review of ERP data. A total of 54 (of 134) studies published between 1972 and 2022 met the criteria for inclusion in the systematic review. Until the beginning of 2022, there was no agreed definition of the ERP; eight definitions of ERP were identified in the literature, complicating the comparison between studies. Additionally, potential risk factors for the shortening of the ERP, including previous anthelmintic use and climate, were frequently not described. Reports of shortened ERP for moxidectin and ivermectin are frequent: 20 studies that used comparable ERP definitions reported shortened moxidectin and ivermectin ERPs of 35 and 28 days, respectively. It is unclear whether the ERPs of these anthelmintics reduced to such levels are due to the development of AR or some biological factors related to horses, cyathostomin species, and/or the environment. The ERPs for other anthelmintics, such as fenbendazole and pyrantel, were frequently not reported due to established resistance against these drugs. Future research in horses is required to understand the mechanism(s) behind the shortening of ERP for cyathostomins. Based on this systematic review, we propose recommendations for future ERP studies.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 28-39"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105024/pdf/main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793052","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":"Molecular characterization and analysis of drug resistance-associated protein enolase 2 of Eimeria tenella","authors":"Yu Yu ,&nbsp;Wenhao Huang ,&nbsp;Qingjie Wang,&nbsp;Hui Dong,&nbsp;Qiping Zhao,&nbsp;Shunhai Zhu,&nbsp;Bing Huang,&nbsp;Hongyu Han","doi":"10.1016/j.ijpddr.2023.01.004","DOIUrl":"10.1016/j.ijpddr.2023.01.004","url":null,"abstract":"<div><p><em>Eimeria tenella</em>, an intestinal parasite, has brought huge economic losses to the poultry industry. The prevalence and severity of the development of drug resistance has increased the challenge of coccidiosis control. We previously identified the enolase 2 of <em>E. tenella</em> (<em>Et</em>ENO2) was differentially expressed in drug-sensitive (DS) and drug-resistant strains using RNA-seq. In this study, the expression of <em>Et</em>ENO2 in diclazuril-resistant (DZR), maduramicin-resistant (MRR), and salinomycin-resistant (SMR) strains was analyzed by quantitative real-time PCR (qRT-PCR) and western blots. <em>Et</em>ENO2 was highly expressed in several drug-resistant strains compared with the DS strain. The qRT-PCR showed that the transcription level of <em>Et</em>ENO2 in the field-isolated resistant strains was upregulated compared with the DS strain. The enzyme activity results indicated that the catalytic activity of <em>Et</em>ENO2 in the drug-resistant strains was higher than in the DS strain. In addition, qRT-PCR and western blots showed that the expression level of <em>Et</em>ENO2 was higher in second generation merozoites (SM) and unsporulated oocysts (UO) than that in sporozoites (SZ) and sporulated oocysts (SO). Immunofluorescence localization revealed that <em>Et</em>ENO2 was distributed throughout SZ and SM and on the surface of the parasites. After the SZ invasion DF-1 cells, it was also observed on the parasitophorous vacuole membrane. Our secretion experiments found that <em>Et</em>ENO2 could be secreted outside the SZ. This study indicated that <em>Et</em>ENO2 might be related to the interaction between <em>E. tenella</em> and host cells and be involved in the development of <em>E. tenella</em> resistance to some anticoccidial drugs.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 81-90"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/51/43/main.PMC9929201.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9810601","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":"Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis","authors":"Roman Memedovski ,&nbsp;Matías Preza ,&nbsp;Joachim Müller ,&nbsp;Tobias Kämpfer ,&nbsp;Reto Rufener ,&nbsp;Marcus Vinicius Nora de Souza ,&nbsp;Emerson Teixeira da Silva ,&nbsp;Gabriel Fernandes de Andrade ,&nbsp;Sophie Braga ,&nbsp;Anne-Christine Uldry ,&nbsp;Natasha Buchs ,&nbsp;Manfred Heller ,&nbsp;Britta Lundström-Stadelmann","doi":"10.1016/j.ijpddr.2023.03.002","DOIUrl":"10.1016/j.ijpddr.2023.03.002","url":null,"abstract":"<div><p>Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm <em>E. multilocularis</em>. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed.</p><p>Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against <em>E. multilocularis in vitro</em> and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against <em>E. multilocularis</em> metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1′681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against <em>E. multilocularis</em>. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 114-124"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9811108","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":"The first report of macrocyclic lactone resistant cyathostomins in the UK","authors":"K.E. Bull ,&nbsp;K.J. Allen ,&nbsp;J.E. Hodgkinson ,&nbsp;L.E. Peachey","doi":"10.1016/j.ijpddr.2023.03.001","DOIUrl":"10.1016/j.ijpddr.2023.03.001","url":null,"abstract":"<div><p>In recent years, resistance to the benzimidazole (BZ) and tetrahydropyrimidine (PYR) anthelmintics in global cyathostomin populations, has led to reliance on the macrocyclic lactone drugs (ML-of which ivermectin and moxidectin are licensed in horses) to control these parasites. Recently, the first confirmed case of resistance to both ivermectin (IVM) and moxidectin (MOX) was reported in the USA in yearlings imported from Ireland. This suggests that ML resistance in cyathostomins has emerged, and raises the possibility that regular movement of horses may result in rapid spread of ML resistant cyathostomins. Resistance may go undetected due to a lack of surveillance for ML efficacy. Here, we report anthelmintic efficacies in cyathostomins infecting UK Thoroughbreds on four studs. Faecal egg count reduction tests (FECRT) were performed to define resistance (resistance = FECR &lt;95% lower credible interval (LCI) &lt; 90%). Stud A yearlings had FECRs of 36.4–78.6% (CI:15.7–86.3) after three IVM treatments, 72.6% (CI: 50.8–85.2) after MOX, and 80.8% (CI: 61.9–90.0) after PYR. Mares on stud A had a FECR of 97.8% (CI: 93.3–99.9) and 98% (95.1–99.4) after IVM and MOX treatment, respectively. Resistance to MLs was not found in yearlings or mares on studs B, C or D with FECR after MOX OR IVM treatment ranging from 99.8 to 99.9% (95.4–100); although yearlings on studs B, C and D all had an egg reappearance period (ERP) of six weeks for MOX and stud C had a four-week ERP for IVM. This study describes the first confirmed case of resistance to both licensed ML drugs on a UK Thoroughbred stud and highlights the urgent need for a) increased awareness of the threat of ML resistant parasites infecting horses, and b) extensive surveillance of ML efficacy against cyathostomin populations in the UK, to gauge the extent of the problem.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 125-130"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a4/fb/main.PMC10036890.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794165","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":"Proteomic characterization of Toxoplasma gondii ME49 derived strains resistant to the artemisinin derivatives artemiside and artemisone implies potential mode of action independent of ROS formation","authors":"Joachim Müller ,&nbsp;Carling Schlange ,&nbsp;Manfred Heller ,&nbsp;Anne-Christine Uldry ,&nbsp;Sophie Braga-Lagache ,&nbsp;Richard K. Haynes ,&nbsp;Andrew Hemphill","doi":"10.1016/j.ijpddr.2022.11.005","DOIUrl":"10.1016/j.ijpddr.2022.11.005","url":null,"abstract":"<div><p>The sesquiterpene lactone artemisinin and its amino-artemisinin derivatives artemiside (GC008) and artemisone (GC003) are potent antimalarials. The mode of action of artemisinins against <em>Plasmodium</em> sp is popularly ascribed to 'activation' of the peroxide group by heme-Fe(II) or labile Fe(II) to generate C-radicals that alkylate parasite proteins. An alternative postulate is that artemisinins elicit formation of reactive oxygen species by interfering with flavin disulfide reductases resposible for maintaining intraparasitic redox homeostasis. However, in contradistinction to the heme-activation mechanism, the amino-artemisinins are effective <em>in vitro</em> against non-heme-degrading apicomplexan parasites including <em>T. gondii</em>, with IC ₅₀ values of 50–70 nM, and induce distinct ultrastructural alterations. However, <em>T. gondii</em> strains readily adapted to increased concentrations (2.5 μM) of these two compounds within few days. Thus, <em>T. gondii</em> strains that were resistant against artemisone and artemiside were generated by treating the <em>T. gondii</em> reference strain ME49 with stepwise increasing amounts of these compounds, yielding the artemisone resistant strain GC003^R and the artemiside resistant strain GC008^R. Differential analyses of the proteomes of these resistant strains compared to the wildtype ME49 revealed that 215 proteins were significantly downregulated in artemisone resistant tachyzoites and only 8 proteins in artemiside resistant tachyzoites as compared to their wildtype. Two proteins, namely a hypothetical protein encoded by ORF TGME49_236950, and the rhoptry neck protein RON2 encoded by ORF TGME49_300100 were downregulated in both resistant strains. Interestingly, eight proteins involved in ROS scavenging including catalase and superoxide dismutase were amongst the differentially downregulated proteins in the artemisone-resistant strain. In parallel, ROS formation was significantly enhanced in isolated tachyzoites from the artemisone resistant strain and – to a lesser extent – in tachyzoites from the artemiside resistant strain as compared to wildtype tachyzoites. These findings suggest that amino-artemisinin derivatives display a mechanism of action in <em>T. gondii</em> distinct from <em>Plasmodium</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 1-12"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9495042","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":"The presence and relative frequency detection of the levamisole-resistance-associated S168T substitution in hco-acr-8 in Haemonchus contortus","authors":"Paulius Baltrušis ,&nbsp;Peter Halvarsson ,&nbsp;Claude L. Charvet ,&nbsp;Johan Höglund","doi":"10.1016/j.ijpddr.2023.02.002","DOIUrl":"10.1016/j.ijpddr.2023.02.002","url":null,"abstract":"<div><p>Parasitic sheep nematodes, among which <em>Haemonchus contortus</em> is often considered to be the most clinically important, exact a significant toll on the animals, not least because of their capacity to evolve drug resistance. Despite decades of research, our understanding of the mechanism of resistance to compounds such as levamisole is fairly limited, which therefore constrains our ability to develop sensitive and efficient molecular diagnostic tools for rapid and accurate resistance detection in field settings. Herein, we investigated the presence and frequency of the newly reported, levamisole-resistance-associated, mutation, yielding a S168T substitution in exon 4 of <em>hco-acr-8</em>, in six different phenotypically described isolates (three susceptible and three resistant), three Swedish field isolates and eight larvae culture samples, the latter two of which originated on farms where levamisole showed complete parasite elimination. For this purpose, we created both an allele-specific and droplet digital PCR approaches and found the mutated allele to be present only in the Kokstad isolate, whereas the other five as well as both the Swedish isolates and larvae cultures displayed only the non-mutated, serine-encoding, allele. While the finding of only the non-mutated allele in the phenotypically susceptible and Swedish isolate and larvae culture samples seemed sensible, we speculate that for the other two phenotypically resistant isolates, different (perhaps secondary) variants are responsible for conferring the resistance to levamisole phenotype, given the polygenic nature of levamisole resistance. All in all, despite the limited number of samples tested here, the mutation causing the S168T substitution in <em>hco-acr-8</em> represents a plausible levamisole resistance-associated variant in, at least, some isolates of <em>H. contortus</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"21 ","pages":"Pages 91-95"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793634","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":"Exploration of the sensitivity to macrocyclic lactones in the canine heartworm (Dirofilaria immitis) in Australia using phenotypic and genotypic approaches","authors":"Rosemonde Isabella Power ,&nbsp;Jan Šlapeta","doi":"10.1016/j.ijpddr.2022.11.003","DOIUrl":"10.1016/j.ijpddr.2022.11.003","url":null,"abstract":"<div><p>Canine heartworm disease is a potentially deadly cardiopulmonary disease caused by the mosquito-borne filarial nematode <em>Dirofilaria immitis</em>. In Australia, the administration of macrocyclic lactone (ML) drugs has successfully reduced the prevalence of <em>D. immitis</em> infection. However, the recent re-emergence of <em>D. immitis</em> in dogs in Queensland, Australia and the identification of ML-resistant isolates in the USA poses an important question of whether ML-resistance has emerged in this parasite in Australia. The aim of this study was to utilise phenotypic and genotypic approaches to examine the sensitivity to ML drugs in <em>D. immitis</em> in Australia. To do this, we surveyed 45 dogs from Queensland and New South Wales across 3 years (2019–2022) for the presence of <em>D. immitis</em> infection using an antigen test, quantitative Modified Knott's test, and qPCR targeting both <em>D. immitis</em> and the <em>D. immitis</em> symbiont <em>Wolbachia</em>. A phenotype observed by utilising sequential quantification of microfilariae for 23/45 dogs was coupled with genetic testing of filtered microfilariae for SNPs previously associated with ML-resistance in isolates from the USA. Sixteen (16/45) dogs tested positive for <em>D. immitis</em> infection despite reportedly receiving ‘rigorous’ heartworm prevention for 12 months prior to the study, according to the owners' assessment. The phenotype and genotypic assays in this study did not unequivocally demonstrate the presence of ML-resistant <em>D. immitis</em> in Australia. Although the failure of 16 dogs to reduce microfilaremia by &gt;90% after ML treatment was considered a suspect phenotype of ML-resistance, no genotypic evidence was discovered using the genetic SNP analysis. The traditional quantitative Modified Knott's test can be substituted by qPCR targeting <em>D. immitis</em> or associated <em>Wolbachia</em> endosymbiont DNA for a more rapid measurement of microfilariae levels. More definitive phenotypic evidence of resistance is critically needed before the usefulness of SNPs for the detection of ML-resistance in Australia can be properly assessed.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"20 ","pages":"Pages 145-158"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9772245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10481241","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}