scholarly journals High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

2021 ◽  
Vol 14 (7) ◽  
pp. 616
Author(s):  
Aya C. Taki ◽  
Joseph J. Byrne ◽  
Tao Wang ◽  
Brad E. Sleebs ◽  
Nghi Nguyen ◽  
...  

Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4156
Author(s):  
Aya C. Taki ◽  
Joseph J. Byrne ◽  
Peter R. Boag ◽  
Abdul Jabbar ◽  
Robin B. Gasser

In the present study, we established a practical and cost-effective high throughput screening assay, which relies on the measurement of the motility of Caenorhabditis elegans by infrared light-interference. Using this assay, we screened 14,400 small molecules from the “HitFinder” library (Maybridge), achieving a hit rate of 0.3%. We identified small molecules that reproducibly inhibited the motility of C. elegans (young adults) and assessed dose relationships for a subset of compounds. Future work will critically evaluate the potential of some of these hits as candidates for subsequent optimisation or repurposing as nematocides or nematostats. This high throughput screening assay has the advantage over many previous assays in that it is cost- and time-effective to carry out and achieves a markedly higher throughput (~10,000 compounds per week); therefore, it is suited to the screening of libraries of tens to hundreds of thousands of compounds for subsequent evaluation and development. The present phenotypic whole-worm assay should be readily adaptable to a range of socioeconomically important parasitic nematodes of humans and animals, depending on their dimensions and motility characteristics in vitro, for the discovery of new anthelmintic candidates. This focus is particularly important, given the widespread problems associated with drug resistance in many parasitic worms of livestock animals globally.


2016 ◽  
Vol 53 (2) ◽  
pp. 120-125 ◽  
Author(s):  
M. Urda Dolinská ◽  
A. Königová ◽  
M. Babják ◽  
M. Várady

SummaryGastrointestinal parasitic nematodes in sheep cause severe economic losses. Anthelmintics are the most commonly used drugs for prophylaxis and therapy against parasitic helminths. The problem of drug resistance has developed for all commercially available anthelmintics in several genera and classes of helminths. In vitro and in vivo tests are used to detect anthelmintic resistance. Two in vitro methods (larval migration inhibition test and micromotility test) for the detection of ivermectin (IVM) resistance were compared using IVM-resistant and IVM-susceptible isolates of Haemonchus contortus. The degree of resistance for each test was expressed as a resistance factor (RF). The micromotility test was more sensitive for quantitatively measuring the degree of resistance between susceptible and resistant isolates. The RFs for this test for IVM and eprinomectin ranged from 1.00 to 108.05 and from 3.87 to 32.32, respectively.


2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Markéta Zajíčková ◽  
Lukáš Prchal ◽  
Martina Navrátilová ◽  
Nikola Vodvárková ◽  
Petra Matoušková ◽  
...  

AbstractHaemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.


2017 ◽  
Author(s):  
Frederick A. Partridge ◽  
Anwen E. Brown ◽  
Steven D. Buckingham ◽  
Nicky J. Willis ◽  
Graham M. Wynne ◽  
...  

AbstractParasitic nematodes infect hundreds of millions of people and farmed livestock. Further, plant parasitic nematodes result in major crop damage. The pipeline of therapeutic compounds is limited and parasite resistance to the existing anthelmintic compounds is a global threat. We have developed an INVertebrate Automated Phenotyping Platform (INVAPP) for high-throughput, plate-based chemical screening, and an algorithm (Paragon) which allows screening for compounds that have an effect on motility and development of parasitic worms. We have validated its utility by determining the efficacy of a panel of known anthelmintics against model and parasitic nematodes:Caenorhabditis elegans, Haemonchus contortus, Teladorsagia circumcincta, andTrichuris muris. We then applied the system to screen the Pathogen Box chemical library in a blinded fashion and identified known anthelmintics, including tolfenpyrad, auranofin, and mebendazole and 14 compounds previously undescribed as anthelmintics, including benzoxaborole and isoxazole chemotypes. This system offers an effective, high-throughput system for the discovery of novel anthelmintics.


Author(s):  
Janneke Wit ◽  
Clayton Dilks ◽  
Erik Andersen

Parasitic nematode infections impact human and animal health globally, especially in the developing world. Anthelmintic drugs are the major line of defense against these infections, but the arsenal is limited. Additionally, anthelmintic resistance is widespread in veterinary parasites and an emerging threat in human parasites. Discoveries of the mode of action of these drugs and mechanisms of resistance have predominantly come from studies of a related non-parasitic nematode species, Caenorhabditis elegans, and the parasitic nematode Haemonchus contortus. Here, we discuss recent progress understanding anthelmintic resistance using these two species and how that progress relates to laboratory and field-based studies of veterinary helminths. We present a powerful approach enabled by the strengths of both nematode species to understand mechanisms of resistance and modes of action of anthelmintic drugs.


2013 ◽  
Vol 33 (2) ◽  
pp. 183-187 ◽  
Author(s):  
Fernanda S. Fortes ◽  
Fernando S. Kloster ◽  
Andressa S. Schafer ◽  
Daniele Bier ◽  
Andréia Buzatti ◽  
...  

Haemonchus contortus is one of the most common and economically significant causes of disease in small ruminants worldwide, and the control programs of parasitic nematodes - including H. contortus - rely mostly on the use of anthelmintic drugs. The consequence of the use of this, as the sole sanitary strategy to avoid parasite infections, was the reduction of the efficacy of all chemotherapeutic products with a heavy selection for resistance. The widespread of anthelmintic resistance and the difficulty of its early diagnosis has been a major concern for the sustainable parasite management on farms. The objective of this research was to determine and compare the ivermectin (IVM) and moxidectin (MOX) effect in a selected field strain of H. contortus with a known resistance status, using the in vitro larval migration on agar test (LMAT). Third stage larvae of the selected isolate were obtained from faecal cultures of experimentally infected sheep and incubated in eleven increasing diluted concentrations of IVM and MOX (6, 12, 24, 48, 96, 192, 384, 768, 1536, 3072 and 6144µg/mL). The dose-response sigmoidal curves were obtained using the R² value of >0.90 and the lethal concentration (LC50) dose for the tested anthelmintic drugs using a four-parameter logistic model. The LC50 value for MOX was significantly lower than IVM (1.253µg/mL and 91.06µg/mL), identifying the H. contortus isolate as considerably less susceptible to IVM compared to MOX. Furthermore, the LMAT showed a high consistency (p<0.0001) and provided to be a useful diagnostic tool for monitoring the resistance status of IVM and MOX in H. contortus field isolate, as well as it may be used for official routine drug monitoring programs under the Ministry of Agriculture (MAPA) guidance.


2020 ◽  
Vol 5 (Special) ◽  

Dubai Health Authority (DHA) is the entity regulating the healthcare sector in the Emirate of Dubai, ensuring high quality and safe healthcare services delivery to the population. The World Health Organization (WHO) declared COVID-19 a pandemic on the 11th of March 2020, indicating to the world that further infection spread is very likely, and alerting countries that they should be ready for possible widespread community transmission. The first case of COVID-19 in the United Arab Emirates was confirmed on 29th of January 2020; since then, the number of cases has continued to grow exponentially. As of 8th of July 2020 (end of the day), 53,045 cases of coronavirus have been confirmed with a death toll of 327 cases. The UAE has conducted over 3,720,000 COVID-19 tests among UAE citizens and residents over the past four months, in line with the government’s plans to strengthen virus screening to contain the spread of COVID-19. There were vital UAE policies, laws, regulations, and decrees that have been announced for immediate implementation to limit the spread of COVID- 19, to prevent panic and to ensure the overall food, nutrition, and well-being are provided. The UAE is amongst the World’s Top 10 for COVID-19 Treatment Efficiency and in the World’s Top 20 for the implementation of COVID-19 Safety measures. The UAE’s mission is to work towards resuming life after COVID-19 and enter into the recovery phases. This policy research paper will discuss the Dubai Health Authority’s rapid response initiatives towards combating the control and spread of COVID-19 and future policy implications and recommendations. The underlying factors and policy options will be discussed in terms of governance, finance, and delivery.


2019 ◽  
Vol 1 (1) ◽  
pp. 72-81
Author(s):  
Hamidreza Shirzadfar ◽  
Narsis Gordoghli

In recent years, chronic medical problems have become increasingly prevalent. Chronic ‎illnesses challenge the view of life as a regular and continuous process, a challenge that has ‎important psychological consequences. The long duration of people suffering from these ‎diseases, the long process of treatment and the fact that there is no proper and definitive ‎treatment for most of these diseases and their associated complications have made chronic ‎diseases a detrimental factor in public health. According to the World Health Organization ‎‎(2006), the prevalence of chronic and non-communicable diseases is increasing in all countries, ‎especially developing countries, so that the major challenge for the health system in the present ‎century, is not living people, but better adapted to chronic illnesses and maintaining their ‎mental and social health and well-being Ed's life-threatening chronic physical illness.‎ Chronic pain is a pain that lasts longer than usual, and according to the criteria of the ‎International Association of Pain, this time is defined as at least 3 months to 6 months. Chronic ‎pain is such that not only faced the sick person whit the pressure of the pain but also with many ‎other pressure that affect different parts of her life. Fibromyalgia is one of the most rheumatologic disorders and one of the most resistant chronic ‎pain syndromes. Fibromyalgia is one of the most common musculoskeletal disorders in adults ‎and chronic pain is one of the most common complaints in this group of patients.


Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 329
Author(s):  
Fu-Sheng Chou ◽  
Krystel Newton ◽  
Pei-Shan Wang

Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.


Author(s):  
Katharina Boldt ◽  
Michaela Coenen ◽  
Ani Movsisyan ◽  
Stephan Voss ◽  
Eva Rehfuess ◽  
...  

The aim of this study was to identify interventions targeting children and their caregivers to reduce psychosocial problems in the course of the COVID-19 pandemic and comparable outbreaks. The review was performed using systematic literature searches in MEDLINE, Embase, PsycINFO and COVID-19-specific databases, including the CDC COVID-19 Research Database, the World Health Organisation (WHO) Global Database on COVID-19 Research and the Cochrane COVID-19 Study Register, ClinicalTrials.gov, the EU Clinical Trials Register and the German Clinical Trials Register (DRKS) up to 25th September 2020. The search yielded 6657 unique citations. After title/abstract and full text screening, 11 study protocols reporting on trials planned in China, the US, Canada, the UK, and Hungary during the COVID-19 pandemic were included. Four interventions targeted children ≥10 years directly, seven system-based interventions targeted the parents and caregivers of younger children and adolescents. Outcome measures encompassed mainly anxiety and depressive symptoms, different dimensions of stress or psychosocial well-being, and quality of supportive relationships. In conclusion, this systematic review revealed a paucity of studies on psychosocial interventions for children during the COVID-19 pandemic. Further research should be encouraged in light of the expected demand for child mental health management.


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