ArticleLiterature Review

New advancement in anthelmintic drugs in veterinary medicine

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Abstract

Anthelmintic treatment of nematode infections remains the mainstay of worm control in farm and companion animals. However, control is threatened by the occurrence of drug resistant nematodes. In recent years, three new anthelmintics have been introduced to the market. Here, we describe the main features including mode of action, availability, spectrum, dose, tolerability, safety, and resistance of emodepside, monepantel, and derquantel.

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... Resistance against most anthelmintic drug classes is widespread and documented for several species (McKellar and Jackson, 2004;Kotze and Prichard, 2016). New anthelmintics with a distinct mode of action can be used to treat populations resistant to multiple anthelmintics, but the introduction of new compounds is rare (Epe and Kaminsky, 2013). One of the newest anthelmintics, the cyclooctadepsipeptide emodepside, has been commercially available since 2007 (Epe and Kaminsky, 2013). ...
... New anthelmintics with a distinct mode of action can be used to treat populations resistant to multiple anthelmintics, but the introduction of new compounds is rare (Epe and Kaminsky, 2013). One of the newest anthelmintics, the cyclooctadepsipeptide emodepside, has been commercially available since 2007 (Epe and Kaminsky, 2013). It is a semisynthetic derivative of a natural metabolite from the fungus Mycelia sterilia . ...
... Emodepside is a broad range anthelmintic with a distinct mode of action compared to other anthelmintics (Epe and Kaminsky, 2013). Previous studies of emodepside sensitivity and phenotypic effects in C. elegans have focussed on the laboratory strain N2 (Willson et al., 2004;Bull et al., 2007;Guest et al., 2007). ...
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Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a large K⁺ conductance (BK) channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1, but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect). We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across natural nematode populations.
... Moreover, drug resistance to recently commercialized anthelmintic drugs (monepantel and derquantel) has already been described (Table 1). To date, drug resistance to tribendimidine and emodepside has not been reported, perhaps because both are used for humans or companion animals only, where resistance in nematodes is not as apparent compared to farm animals [32]. There are several possible drug resistance mechanisms in nematodes: (i) a reduction in the number of receptors, (ii) a deletion or mutation of amino acid(s) (AA) in the gene encoding the drug target, (iii) the absence of bioactivating enzymes. ...
... It inhibited hatching and embryo development with an IC50 of 24 μg/mL (164.3 μM) [78]. (5,6,7,17,19,26,27,28,31,32,33,34,36), saponin (4,25), terpenoids (12,13,15,16,18,37), alkaloids (1,2,3,8,9), coumaric acid (14,29,30), miscellaneous (10,11,20,21,22,24). ...
... The authors concluded that plants from the Leguminosae family may offer an alternative source for the control of gastrointestinal nematodes of small ruminants. (23), phenolics (5,6,7,17,19,26,27,28,31,32,33,34,36), saponin (4,25), terpenoids (12,13,15,16,18,37), alkaloids (1,2,3,8,9), coumaric acid (14,29,30), miscellaneous (10,11,20,21,22,24). ...
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Intestinal parasitic nematodes infect approximately two billion people worldwide. In the absence of vaccines for human intestinal nematodes, control of infections currently relies mainly on chemotherapy, but resistance is an increasing problem. Thus, there is an urgent need for the discovery and development of new anthelmintic drugs, especially ones with novel mechanisms of action. Medicinal plants hold great promise as a source of effective treatments, including anthelmintic therapy. They have been used traditionally for centuries and are mostly safe (if not, their toxicity is well-known). However, in most medicinal plants the compounds active against nematodes have not been identified thus far. The free-living nematode C. elegans was demonstrated to be an excellent model system for the discovery of new anthelmintics and for characterizing their mechanism of action or resistance. The compounds discussed in this review are of botanical origin and were published since 2002. Most of them need further studies of their toxicity, mechanisms and structure-activity relationship to assess more fully their potential as drugs.
... The following years, between 1960 and 1980, witnessed an extraordinary achievement in the development of anthelmintic drugs [10]. Despite this, very few anthelmintic drugs were discovered in the recent years to combat helminth infections [12]. However, a variety of diseases caused by helminths, including larval cestode infections in animals, still await satisfactory treatment and, unfortunately, the extensive use and improper dosage of anthelmintics in conjunction with other factors has resulted in drug resistance, causing a serious threat to effective control of helminth infections [13]. ...
... Veterinary anthelmintics available to treat veterinary helminthiasis belong to the classes of probenzimidazoles and benzimidazoles, macrocyclic lactones, imidazothiazoles, salicylanilides and substituted phenols, tetrahydropyrimidines, spiroindoles, amino-acetonitrile derivatives and Cyclooctadepsipeptides [10,12,[48][49][50]. ...
... This drugs acts via stimulation of pharyngeal paralysis through inhibition of Ca 2+ influx into the muscle cells of the pharynx and eventual death of the parasite [70]. It is available as a spot-on for cats and tablet for dogs for the treatment of GI nematodes [12]. ...
Article
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Helminths are a diverse group of parasitic worms in the body of animals and human. Infection of livestock with parasitic worms poses a great burden on the health of animals that eventually leads to great losses in the productivity of these animals and economic losses to the farmers. The control of helminthiasis is dependent almost solely on the use of anthelmintic drugs, due to the ease of implementation and low cost of therapy, compared to other methods of control. However, chemotherapy of parasitic worms is burdened with such problems as the development of anthelmintic resistance (AR). Many of the currently available anthelmintic drugs have been in use for quite a long time and reports exhibiting the development of AR against them are increasing. Improving livestock management and, hence, productivity is a requirement in order to compensate for the increasing world population, which will eventually lead to increased demands for animal products. The tackling of AR needs to implement such methods as: (i) the systematic use of the currently available drugs, (ii) control of animal pasture, (iii) promoting the breeding of animals that are naturally resistant to certain types of helminths and (iv) development of new anthelmintic drugs by the pharmaceutical industry that have novel modes of action. Although each of these methods plays a part in the control program, chemotherapy will remain the cornerstone in the control program of helminth infections. Hence, the continuous supply of new antiparasitic compounds to the currently available anthelmintic pool is the best strategy to be implemented in the fight against helminth infections.
... Anthelmintic drug discovery has been a continued emphasis in the animal health industry, driven by the spread of resistance to the macrocyclic lactones [2]. In the past 25 years, three new classes of anthelmintic drugs have reached the market: derquantel, emodepside and monepantel. ...
... Since then only moxidectin (8,2018) and triclabendazole (9, 2019) have been approved. The major drugs used for control of human helminth infections have been in clinical use for many years: ivermectin (7, FDA approval in 1996), mebendazole (2,1974), albendazole (1,1996), praziquantel (5,1982), diethylcarbamazine (6,1950). The scarcity of new drugs reflects the limited economic incentive to spur commercial investment in neglected tropical diseases such as human helminth infection. ...
Article
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Helminths, including cestodes, nematodes and trematodes, are a huge global health burden, infecting hundreds of millions of people. In many cases, existing drugs such as benzimidazoles, diethylcarbamazine, ivermectin and praziquantel are insufficiently efficacious, contraindicated in some populations, or at risk of the development of resistance, thereby impeding progress towards World Health Organization goals to control or eliminate these neglected tropical diseases. However, there has been limited recent progress in developing new drugs for these diseases due to lack of commercial attractiveness, leading to the introduction of novel, more efficient models for drug innovation that attempt to reduce the cost of research and development. Open science aims to achieve this by encouraging collaboration and the sharing of data and resources between organisations. In this review we discuss how open science has been applied to anthelmintic drug discovery. Open resources, including genomic information from many parasites, are enabling the identification of targets for new antiparasitic agents. Phenotypic screening remains important, and there has been much progress in open-source systems for compound screening with parasites, including motility assays but also high content assays with more detailed investigation of helminth physiology. Distributed open science compound screening programs, such as the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has been much progress in creating more potent and selective derivatives. This work exemplifies how open science approaches can catalyse drug discovery against neglected diseases.
... Efforts towards developing novel anthelmintics are relatively limited, despite the increased need to reduce the subclinical, clinical and economic burden associated with helminth infections [8,9]. Existing anthelmintic drugs include the chemical classes benzimidazoles, imidazothiazoles and macrocyclic lactones [10]. Over the past decades, only few new classes of anthelmintics have been discovered and approved, and only three new scaffolds have made it into the market since 2007 [10]: cyclodepsipeptides (e.g. ...
... Existing anthelmintic drugs include the chemical classes benzimidazoles, imidazothiazoles and macrocyclic lactones [10]. Over the past decades, only few new classes of anthelmintics have been discovered and approved, and only three new scaffolds have made it into the market since 2007 [10]: cyclodepsipeptides (e.g. emodepside), which are currently restricted to use in companion animals; amino-acetonitrile derivatives (e.g. ...
Article
Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78-22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
... In parasitic nematodes, EMO interferes with latrophilin receptors (6,7) and SLO-1 calcium-activated potassium channels (8), leading to paralysis of the pharynx and body-wall muscles, and finally resulting in inhibition of locomotion, feeding, and egg-laying (7,9,10). In contrast, EMO has a low acute toxicity in target animals (5,11) and normally does not enter the brain of vertebrate species due to drug efflux at the blood-brain barrier via the multidrug resistance (MDR1, syn. ABCB1) efflux transporter (12). ...
... In contrast, pharmacodynamic interactions of EMO with vertebrate central nervous system (CNS) receptors are scarcely understood. Nevertheless, it is wellestablished that EMO has a low toxicity in mammals (11,(23)(24)(25)(26)(27). In the present case, however, there is a suspected adverse reaction related to the administration of Profender R . ...
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A 3-year-old male Australian Shepherd was presented with signs of neurological toxicity following the administration of Profender® at the recommended dosage. Unfortunately, the owner had received the product from a veterinarian without any further instructions on fasting as recommended by the manufacturer, so the dog was fed prior to Profender® administration. Neurological toxicity included generalized tremor, agitation and panting, and required hospitalization of the dog. All neurological signs resolved after symptomatic treatment within 24 h and the dog was discharged without the need for further medication. MDR1 genotyping revealed a homozygous mutation of the MDR1 gene, which is normally important to prevent brain penetration of emodepside by an efflux-based transport mechanism at the blood brain barrier. This case indicates that Profender® can lead to serious, but transient neurological toxicity in dogs with homozygous MDR1 mutation even at therapeutic dosage, in particular when fasting recommendations are disregarded. Therefore, the case report highlights both the importance of MDR1 genotyping in predisposed dog breeds as well as strict compliance with fasting recommendations around the time of Profender® administration.
... Such drugs include aminoacetonitrile derivatives (e.g. monepantel), aminophenylamidines (tribendimidine), benzimidazoles (albendazole), imidazothiazoles (levamisole), macrocyclic lactones (ivermectin and moxidectin), spiroindoles (derquantel) and tetrahydropyrimidines (morantel, oxantel and pyrantel) [10,11]. ...
... [12]). Novel classes of anthelmintics, including an aminoacetonitrile (monepantel), a cyclooctadepsipeptide (emodepside) and a spiroindole (derquantel), have become available relatively recently [10,11]. Their mode of action involves binding to neural acetylcholine receptors (monepantel) [15], to voltage-/ calcium-dependent potassium channels and to G-protein-coupled latrophilin-like receptors (emodepside) [16] or B-subtype nicotinic acetylcholine receptors in muscle cells (derquantel) [17], resulting in spastic (monepantel) or flaccid (emodepside and derquantel) paralysis of sensitive nematodes, leading to death or elimination from the host animal. ...
Article
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Here, the scientific and patent literature on the activities of purified natural compounds has been reviewed, with the aim of assessing their suitability as anthelmintic drug discovery starting points. Only compounds described as active against parasitic nematodes of animals or against the model nematode Caenorhabditis elegans have been analysed. Scientific articles published since 2010 and patents granted from 2000, both inclusive, have been included in this analysis. The results show a scarcity of novel chemical structures, a limited follow-up of compounds disclosed before 2010 and a bias towards the screening of plant products, almost to the exclusion of other sources, when microbial extracts have, historically, provided most starting points for anti-infective drugs. All plant products published in this period were previously known, alerting to the high re-discovery rates of a limited number of chemical classes from this source. The most promising compounds described in the literature reviewed here, namely the linear nemadectin-derivatives, are novel and of bacterial origin. Patented but otherwise unpublished spiroketal structures also appear as interesting scaffolds for future development. The patent literature confirmed that it is possible to patent derivatives of previously known products, making them valid starting points for translational research.
... Emodepside, is a broad-spectrum veterinary anthelmintic licensed under the name of Profender ® and Procox ® and is used in combination with praziquantel and toltrazuril, respectively [17]. Its activity has been demonstrated against a wide range of nematodes in the veterinary field [18][19][20][21][22][23][24][25]. Repurposing emodepside for human use started more than ten years ago with preclinical studies against filarial nematodes which may be considered surrogates of human filarial infections [26]. ...
... Both the larval and the adult nematode and schistosome stages were screened phenotypically in presence of emodepside over a time course of 72 hours followed by in vivo studies. As emodepside belongs to the group of cyclooctadepsipeptides that are known to be very active against different animal gastrointestinal nematodes and filarial parasites, good antinematicidal activity was expected [20,30,[37][38][39][40]. The drug showed a high efficacy in vitro against all the nematode species and was highly effective against the two hookworms (A. ...
Article
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Background Helminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Emodepside, a marketed broad-spectrum veterinary anthelminthic with a unique mechanism of action, undergoing development for onchocerciasis is an interesting anthelmintic drug candidate. We tested the in vitro and in vivo activity of emodepside on nematode species that serve as models for human soil-transmitted helminth infection as well as on schistosomes. Methods In vitro viability assays were performed over a time course of 72 hours for Trichuris muris, Necator americanus, Ancylostoma ceylanicum, Heligmosomoides polygyrus, Strongyloides ratti, Schistosoma mansoni and Schistosoma haematobium. The drug effect was determined by the survival rate for the larvae and by phenotypical scores for the adult worms. Additionally, mice infected with T. muris and hamsters harboring hookworm infection (N. americanus or A. ceylanicum) were administered orally with emodepside at doses ranging from 1.25 to 75 mg/kg. Expelled worms in the feces were counted until 3 days post-drug intake and worms residing in the intestines were collected and counted after dissection. Results After 24 hours, emodepside was very active in vitro against both larval and adult stages of the nematodes T. muris, A. ceylanicum, N. americanus, H. polygyrus and S. ratti (IC50 < 4 µM). The good in vitro activity was confirmed in vivo. Hamsters infected with the hookworms were cured when administered orally with 2.5 mg/kg of the drug. Emodepside was also highly active in vivo against T. muris (ED50 = 1.2 mg/kg). Emodepside was moderately active on schistosomula in vitro (IC50 < 8 µM) 24 h post-drug incubation and its activity on adult S. mansoni and S. haematobium was low (IC50: 30–50 µM). Conclusions Emodepside is highly active against a broad range of nematode species both in vitro and in vivo. The development of emodepside for treating soil-transmitted helminth infections should be pursued.
... Thus, parasitic nematode infections are a substantial burden to animal health and livestock production. Currently, anthelmintic treatment remains the mainstay of control for parasitic nematodes [6,7]. The occurrence of anthelmintic resistance, together with the limited number of anthelmintics being commercialised, indicates an urgency to discover new and effective anthelmintic compounds [6,8,9]. ...
... Currently, anthelmintic treatment remains the mainstay of control for parasitic nematodes [6,7]. The occurrence of anthelmintic resistance, together with the limited number of anthelmintics being commercialised, indicates an urgency to discover new and effective anthelmintic compounds [6,8,9]. ...
Article
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Background: In partnership with the Medicines for Malaria Venture (MMV), we screened a collection ('Stasis Box') of 400 compounds (which have been in clinical development but have not been approved for illnesses other than neglected infectious diseases) for inhibitory activity against Haemonchus contortus, in order to attempt to repurpose some of the compounds to parasitic nematodes. Methods: We assessed the inhibition of compounds on the motility and/or development of exsheathed third-stage (xL3s) and fourth-stage (L4) larvae of H. contortus using a whole-organism screening assay. Results: In the primary screen, we identified compound MMV690767 (also known as SNS-032) that inhibited xL3 motility by ~70% at a concentration of 20 μM after 72 h as well as compound MMV079840 (also known as AG-1295), which induced a coiled xL3 phenotype, with ~50% inhibition on xL3 motility. Subsequently, we showed that SNS-032 (IC50 = 12.4 μM) and AG-1295 (IC50 = 9.92 ± 1.86 μM) had a similar potency to inhibit xL3 motility. Although neither SNS-032 nor AG-1295 had a detectable inhibitory activity on L4 motility, both compounds inhibited L4 development (IC50values = 41.24 μM and 7.75 ± 0.94 μM for SNS-032 and AG-1295, respectively). The assessment of the two compounds for toxic effects on normal human breast epithelial (MCF10A) cells revealed that AG-1295 had limited cytotoxicity (IC50 > 100 μM), whereas SNS-032 was quite toxic to the epithelial cells (IC50 = 1.27 μM). Conclusions: Although the two kinase inhibitors, SNS-032 and AG-1295, had moderate inhibitory activity on the motility or development of xL3s or L4s of H. contortus in vitro, further work needs to be undertaken to chemically alter these entities to achieve the potency and selectivity required for them to become nematocidal or nematostatic candidates.
... For the treatment of nematodes, a variety of drugs are in use, and new ones have been introduced to the market recently. However, spread of resistance is a major problem in the veterinary sector [6]. For treatment of cestode and trematode infections, praziquantel (PZQ) is the drug of choice against most species [7]. ...
... For motility measurement, two separate images were taken of each well at a 10 seconds interval and at 40 times magnification. Motility was assessed at various time points (1,6,12,18, and 24 h) after addition of compounds. The motility index for each well, resulting from differences in pixels within the 10 seconds interval, was calculated with a pixel grey value threshold of 230 in Ima-geJ version 1.49 (the respective Macro including details of calculation is given in S2 File). ...
Article
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Intestinal cestodes are infecting millions of people and livestock worldwide, but treatment is mainly based on one drug: praziquantel. The identification of new anti-cestodal compounds is hampered by the lack of suitable screening assays. It is difficult, or even impossible, to evaluate drugs against adult cestodes in vitro due to the fact that these parasites cannot be cultured in microwell plates, and adult and larval stages in most cases represent different organisms in terms of size, morphology, and metabolic requirements. We here present an in vitro-drug screening assay based on Echinococcus multilocularis protoscoleces, which represent precursors of the scolex (hence the anterior part) of the adult tapeworm. This movement-based assay can serve as a model for an adult cestode screen. Protoscoleces are produced in large numbers in Mongolian gerbils and mice, their movement is measured and quantified by image analysis, and active compounds are directly assessed in terms of morphological effects. The use of the 384-well format minimizes the amount of parasites and compounds needed and allows rapid screening of a large number of chemicals. Standard drugs showed the expected dose-dependent effect on movement and morphology of the protoscoleces. Interestingly, praziquantel inhibited movement only partially within 12 h of treatment (at concentrations as high as 100 ppm) and did thus not act parasiticidal, which was also confirmed by trypan blue staining. Enantiomers of praziquantel showed a clear difference in their minimal inhibitory concentration in the motility assay and (R)-(-)-praziquantel was 185 times more active than (S)-(-)-praziquantel. One compound named MMV665807, which was obtained from the open access MMV (Medicines for Malaria Venture) Malaria box, strongly impaired motility and viability of protoscoleces. Corresponding morphological alterations were visualized by scanning electron microscopy, and demonstrated that this compound exhibits a mode of action clearly distinct from praziquantel. Thus, MMV665807 represents an interesting lead for further evaluation.
... We observed 411 different patterns of susceptibility (strain rank order) between levamisole and Cry5B, indicating 412 that this combined therapy could be an effective drug combination. Another promising 413 combination therapy is derquantel and abamectin [56,57]. Derquantel and abamectin have been 414 used in combination to treat multi-drug resistant Haemonchus contortus [58,59]. ...
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Treatment of parasitic nematode infections in humans and livestock relies on a small arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed significant variation in anthelmintic responses across drug classes. Dose-response trends within a drug class showed that the C. elegans strains elicited similar responses within the benzimidazoles but variable responses in the macrocyclic lactones and nicotinic acetylcholine receptor agonists. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC 10 ) and slope estimates of each dose-response curve of each strain to the reference strain, N2, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides. Third, we quantified the heritability of responses to each anthelmintic and observed a significant correlation between exposure closest to the EC 10 and the exposure that exhibited the most heritable responses. Heritable genetic variation can be explained by strain-specific anthelmintic responses within and across drug classes. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes. AUTHOR SUMMARY Parasitic nematodes infect most animal species and significantly impact human and animal health. Control of parasitic nematodes in host species relies on a limited collection of anthelmintic drugs. However, anthelmintic resistance is widespread, which threatens our ability to control parasitic nematode populations. Here, we used the non-parasitic roundworm Caenorhabditis elegans as a model to study anthelmintic resistance across 26 anthelmintics that span ten drug classes. We leveraged the genetic diversity of C. elegans to quantify anthelmintic responses across a range of doses, estimate dose-response curves, fit strain-specific model parameters, and calculate the contributions of genetics to these parameters. We found that genetic variation within a species plays a considerable role in anthelmintic responses within and across drug classes. Our results emphasize how the incorporation of genetically diverse C. elegans strains is necessary to understand anthelmintic response variation found in natural populations. These results highlight drugs to prioritize in future mapping studies to identify genes involved in anthelmintic resistance. GRAPHICAL ABSTRACT
... However, communal ownership of farmlands in most communities in the tropics limits their use for controlled grazing (Githiori et al., 2003). Consequently, anthelmintic intervention remains the most effective means of controlling the disease, but their continuous use and efficacy are limited by the unaffordability of the drugs, their uncertain availability, and the emergence of worm strains that are resistant to the available drugs (Epe & Kaminsky, 2013). In addition, there has been an increasing concern over chemical residues in edible animal products associated with the use of anthelmintic drugs in livestock (Waller, 1997). ...
Article
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Aim of study: To investigate the in vitro anthelmintic efficacies of three plants, Annona senegalensis (AS), Cochlospermum planchonii (CP), and Sarcocephalus latifolius (SL), used by livestock farmers in Northern Nigeria, to treat gastrointestinal nematode infections in ruminants. Area of study: Makurdi, Benue State, Nigeria. Materials and methods: The plants were selected through a structured questionnaire administered to livestock farmers in Northern Nigeria. Aqueous and acetone leaf (AS and SL) and root (CP) extracts of these plants were investigated for their anthelmintic activity against Haemonchus contortus using the egg hatch inhibition assay at concentration levels of 0.3125 to 10 mg/mL in 2.5% dimethyl sulfoxide. Main results: A probit log-dose response analysis showed that acetone extract of CP achieved 100% egg hatch inhibition similar to the commercial drug at all tested concentrations after 48 hours of incubation, while AS demonstrated 88.7% egg hatch inhibition. Acetone extract of SL had less than 50% egg hatch inhibition at all tested concentrations. On the other hand, the aqueous extract of CP and SL both exhibited 100% inhibition at 5 and 10 mg/mL of the tested concentrations, while AS had less than 50% egg hatch inhibition at all tested concentrations. Research highlights: This study identified CP, AS, and SL as medicinal plants with rich sources of molecules that have potential value in the development of novel anthelmintic drugs.
... This is particularly necessary due to the increasingly encountered problem of anthelmintic resistance in parasitic nematodes [4][5][6][7]. New drugs, as alternatives to the established antiparasitics, as well as vaccines and new control measures are not available for equines or receive little research attention [7,8]. Strategic deworming of horses, i.e. regular deworming at fixed times of the year without prior diagnosis, is still standard on many horse farms, which leads to the treatment of horses that have low or no detectable parasite burdens [9][10][11][12]. ...
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Background Due to high prevalence of anthelmintic resistance in equine helminths, selective treatment is increasingly promoted and in some countries a positive infection diagnosis is mandatory before treatment. Selective treatment is typically recommended when the number of worm eggs per gram faeces (epg) exceeds a particular threshold. In the present study we compared the semi-quantitative sedimentation/flotation method with the quantitative methods Mini-FLOTAC and FECPAK G2 in terms of precision, sensitivity, inter-rater reliability and correlation of worm egg counts to improve the choice of optimal diagnostic tools. Methods Using sedimentation/flotation (counting raw egg numbers up to 200), we investigated 1067 horse faecal samples using a modified Mini-FLOTAC approach (multiplication factor of 5 to calculate epgs from raw egg counts) and FECPAK G2 (multiplication factor of 45). Results Five independent analyses of the same faecal sample with all three methods revealed that variance was highest for the sedimentation/flotation method while there were no significant differences between methods regarding the coefficient of variance. Sedimentation/flotation detected the highest number of samples positive for strongyle and Parascaris spp. eggs, followed by Mini-FLOTAC and FECPAK G2 . Regarding Anoplocephalidae, no significant difference in frequency of positive samples was observed between Mini-FLOTAC and sedimentation/flotation. Cohen’s κ values comparing individual methods with the combined result of all three methods revealed almost perfect agreement (κ ≥ 0.94) for sedimentation/flotation and strong agreement for Mini-FLOTAC (κ ≥ 0.83) for strongyles and Parascaris spp. For FECPAK G2 , moderate and weak agreements were found for the detection of strongyle (κ = 0.62) and Parascaris (κ = 0.51) eggs, respectively. Despite higher sensitivity, the Mini-FLOTAC mean epg was significantly lower than that with FECPAK G2 due to samples with > 200 raw egg counts by sedimentation/flotation, while in samples with lower egg shedding epgs were higher with Mini-FLOTAC than with FECPAK G2 . Conclusions For the simple detection of parasite eggs, for example, to treat foals infected with Parascaris spp., sedimentation/flotation is sufficient and more sensitive than the other two quantitative investigared in this study. Mini-FLOTAC is predicted to deliver more precise results in faecal egg count reduction tests due to higher raw egg counts. Finally, to identify animals with a strongyle epg above a certain threshold for treatment, FECPAK G2 delivered results comparable to Mini-FLOTAC. Grpahical Abstract
... Родственные отношения между основными 16-членными макролидами мильбемицинами и авермектинами продемонстрированы на рис. 2 [38]. 12 Структурная новизна авермектинов и их огромное экономическое значение привлекают большое внимание исследовательских групп, занимающихся химической модификацией и полным синтезом этих соединений, а также совершенствованием существующих методов биосинтеза [42,43]. ...
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Parasitic diseases are a serious problem for medicine and the agro-industrial complex. The most effective antiparasitic compounds are avermectins, for the discovery of which Satoshi Omura and William Campbell were awarded the 2015 Nobel Prize in Physiology or Medicine. For the first time, the monograph summarizes and analyzes the achievements in the chemistry of avermectins and milbemycins, as well as analyzes the possible directions and patterns of chemical modification of these compounds. In addition, the analysis of data on the relationship «structure-property» allows a more conscious approach to the modification of these compounds in order to increase their biological activity, stability, etc. The monograph is intended for wide range of specialists in the field of chemistry of natural compounds and biologically active substances.
... Anthelmintics are still the first choice for the treatment and prophylaxis of nematode infection [13] and new classes of "resistance-busting" anthelmintics (emodepside, monepantel, and derquantel) have been released into the market [4,14]. However, resistance to anthelmintic drugs is growing [15,16]. ...
Article
Ion channels are important targets of anthelmintic agents. In this study, we identified 3 types of ion channels in Ascaris suum tissue incorporated into planar lipid bilayers using an electrophysiological technique. The most frequent channel was a large-conductance cation channel (209 pS), which accounted for 64.5% of channels incorporated (n=60). Its open-state probability (Po) was ~0.3 in the voltage range of –60~+60 mV. A substate was observed at 55% of the main-state. The permeability ratio of Cl- to K+ (PCl/PK) was ~0.5 and PNa/PK was 0.81 in both states. Another type of cation channel was recorded in 7.5% of channels incorporated (n=7) and discriminated from the large-conductance cation channel by its smaller conductance (55.3 pS). Its Po was low at all voltages tested (~0.1). The third type was an anion channel recorded in 27.9% of channels incorporated (n=26). Its conductance was 39.0 pS and PCl/PK was 8.6±0.8. Po was ~1.0 at all tested potentials. In summary, we identified 2 types of cation and 1 type of anion channels in Ascaris suum. Gating of these channels did not much vary with voltage and their ionic selectivity is rather low. Their molecular nature, functions, and potentials as anthelmintic drug targets remain to be studied further.
... Its mode of action is different from the other available anthelmintic families since it acts as a positive allosteric modulator of the nematode specific acetylcholine receptor MPTL-1 (Rufener et al., 2009(Rufener et al., , 2010. MNP binding to this receptor results in a constant uncontrolled flux of ions and finally in a depolarization of muscle cells leading to nematode paralysis (Epe and Kaminsky, 2013). The cellular target of MNP, the MPTL-1 receptor, is so far only present in nematodes, which might explain the excellent tolerability of MNP in mammals and its high efficacy against multidrug-resistant parasites to other anthelmintic classes in sheep and cattle (Baker et al., 2012;King et al., 2015). ...
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The goal of the current work was to perform an integrated evaluation of monepantel (MNP) pharmacokinetics (PK) and pharmacodynamics, measured as anthelmintic efficacy, after its oral administration to calves naturally infected with GI nematodes resistant to ivermectin (IVM) and ricobendazole (RBZ) on three commercial farms. On each farm, forty-five calves were randomly allocated into three groups (n = 15): MNP oral administration (2.5 mg/kg); IVM subcutaneous (SC) administration (0.2 mg/kg); and RBZ SC administration (3.75 mg/kg). Eight animals from the MNP treated group (Farm 1) were selected to perform the PK study. Drug concentrations were measured by HPLC. The efficacy was determined by the faecal egg count reduction test (FECRT). MNP and MNP-sulphone (MNPSO2) were the main analytes recovered in plasma. MNPSO2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO2 metabolite (96.8 ± 29.7 ng/mL and 9220 ± 1720 ng h/mL) compared to MNP (21.5 ± 4.62 ng/mL and 1709 ± 651 ng h/mL). The MNPSO2 AUC value was 6-fold higher compared to the parent drug. Efficacies of 99% (Farm 1), 96% (Farm 2) and 98% (Farm 3) demonstrated the high activity of MNP (P
... High variations in dosage resulting from the splitting revealed for some of the studied tablets could cause clear risks to the health of the treated animals. For example, the unfeasibility observed in splitting FE/CH, which contains fenbendazole, could result in the administration of subtherapeutic doses of this drug, and as a consequence would not stop the parasitic infection's progress, facilitating the development of a resistance mechanism in the parasites and leading to more severe developments of these infections (43). The administration of higher doses, on the other hand, could cause the appearance of adverse reactions, which in the case of this drug include vomiting, diarrhea, compromised immune system, and reduced fertilization levels of the animal (44). ...
Article
It is well known that the splitting of tablets can bring serious risks to the health of the treated animals, e.g., the possible adverse reactions caused by overdoses of fenbendazole or aspirin. In this regard, this work aimed to evaluate, for the first time, the splitting behavior of commercial veterinary tablets and identifying the technological aspects that interfere in this process. Tablets were cut in halves using a tablet splitter and were analyzed regarding mass variation, mass loss, friability, and hardness. Microstructural and morphological evaluations were also performed. For most of the tablets, organic flavor additives provided more uniformity and cohesive matrix, which preserved its hardness after the cut and led to subdivision results within acceptable limits for mass measurements and friability. Apart from the microstructure, the most critical technological aspect for a correct splitting performance in such tablets was the presence of a score. Thus, the results presented here allow us to guide the manufacturing of veterinary drug products in order to produce tablets more adapted to the splitting process.
... The macrocyclic lactones (avermectins and milbemycins) interact with glutamate gated chloride channels (Pemberton et al., 2001;Wolstenholme and Rogers, 2005;Geary and Moreno, 2012), while the cholinomimetics, including levamisole and pyrantel act on nicotinic acetylcholine receptors (Pinnock et al., 1988;Robertson and Martin, 1993) and emodepside acts on voltage-gated potassium channels (Guest et al., 2007;Kulke et al., 2014;Crisford et al., 2015;Kashyap et al., 2019). Other relatively new compounds such as derquantel (Ruiz-Lancheros et al., 2011;Epe and Kaminsky, 2013), monepantel (Kaminsky et al., 2011;Abongwa et al., 2018) and tribendimidine (Keiser et al., 2007;Hu et al., 2009;Robertson et al., 2015) also act on nematode nicotinic acetylcholine receptors (Bartos et al., 2006;Holden-Dye et al., 2013;Martin et al., 2015). ...
Article
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Despite being considered one of the most pathogenic helminth infections of companion animals, members of macrocyclic lactone class are the only drugs available for the prevention of heartworm disease caused by Dirofilaria immitis. Alarmingly, heartworm prevention is at risk; several studies confirm the existence of macrocyclic lactone resistance in D. immitis populations across the United States. To safeguard the long term prevention and control of this disease, the identification and development of novel anthelmintics is urgently needed. To identify novel, resistance-breaking drugs, it is highly desirable to: Unfortunately, none of the three above statements can be answered sufficiently for D. immitis and most of our hypotheses derive from surrogate species and/or in vitro studies. Therefore, the present study aims to improve our fundamental understanding of the neuromuscular system of the canine heartworm by establishing new methods allowing the investigation of body wall and pharyngeal muscle responses and their modulation by anthelmintics. We found that the pharynx of adult D. immitis responds to both ivermectin and moxidectin with EC50s in the low micromolar range. We also demonstrate that the somatic muscle cells have robust responses to 30 μM acetylcholine, levamisole, pyrantel and nicotine. This is important preliminary data, demonstrating the feasibility of electrophysiological studies in this important parasite.
... However, resistance to these drugs is becoming widespread because of the relatively few chemically dissimilar groups of AH available for the last many decades and their misuse (Aiello et al., 2005). As a solution, the new advancement in veterinary AH reported in some European countries, such as Switzerland (Epe and Kaminsky, 2013), which advocates the uses of new AH drugs that have new mode of action is a promising step to combat AH resistance. ...
Thesis
Trichostrongylus colubriformis is one of the major gastro intestinal nematodes (GINs), which cause severe morbidity and mortality in small ruminants worldwide. This comparative study on the infection profile of sheep and goats with an intestinal worm Trichostrongylus colubriformis was aimed to assess the performance of the parasite and the responses of the hosts. It also evaluated the effect of a local isolate of nematophagus fungus species, Arthrobotrys oligospora on the L3 of the parasite in vitro. A total of 14 sheep and 14 goats were employed in such a way that half of them were drenched with 10000 L3/animal and the remaining halves were uninfected controls. The infection profile and impacts of infection on the animals were assessed by measuring faecal egg count, packed cell volume and body weight gain for up to 8 weeks. After 8 weeks of infection, experimental animals were killed in humane manner, worms were recovered from the intestines, counted, and worm burdens were In addition, nematophagous fungus (Arthrobotrys oligospora) was used for in vitro trial against L3 after incubating the fungus and the worms in potato dextrose agar supplemented with 0.05% chloramphenicol. Accordingly, faecal egg count at 18, 45, 52 and 56 days post infection was significantly higher in goats than in sheep, and so is worm burden at the end of the study (P<0.05). Packed cell volume was significantly reduced in both sheep and goats (P<0.05). However, it came back to normal earlier in sheep while it remained significantly lower than the value of control in infected goats. Goats experienced significantly lower weight gain compared with sheep. In vitro trial revealed, Arthrobotrys oligospora reduced survival of 84% of infective larvae after 10 days incubation. In conclusion, sheep performed better than goats to the impacts of experimental infection by T. colubriformis based on assessed parameters. Efficacy of the local strain of A. oligospora is a promising step for future biological control options against nematodes. Therefore, husbandry management of small ruminants particularly goats, in which infection results in severe production loss, in the areas where T. colubriformis prevails should use local epidemiological knowledge and focus on minimizing the exposure to infective stage in the field. A wide scale in vitro trail and further in vivo studies about efficacy of Arthrobotrys oligospora against T. colubriformis and other GINs is also recommended. Key words:, Arthrobotrys oligospora, Experimental infection, , Goat, Sheep, T. colubriformis
... Currently, the control of parasitic helminths relies chiefly on the use of synthetic, broad-spectrum anthelmintic drugs. In all, major classes anthelmintics commercially available include benzimidazoles, macrocyclic lactones, nicotinic agonists, amino-acetonitrile derivatives and spiroindol [4]. However, some of these drugs are expensive, and as such unaffordable to livestock farmers in resourceconstrained developing nations. ...
Article
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Medicinal plants are promising, as source of alternative solution to the problem of parasitic helminth infections that hamper the sustainable supply of products from farm animals. Ocimum gratissimum and Cymbopogon citratus leaves are commonly used internally to treat worms, relieve abdominal pains and stomach ache. This study, therefore, evaluated their leaf extracts for anthelmintic activity against Haemonchus placei worm from cattle; the most active extract being subjected to phytochemical analysis. The extracts, obtained by maceration using acetone, were evaluated for anthelmintic activity by exposing adult H. placei to a range of concentrations (5-60 mg/mL) for 3 hours and then counting the number of confirmed dead worms. Anthelmintic activity data were fitted to a non-linear regression equation (Log [extract] vs. response; variable slope) to produce best-fit sigmoidal curves from which LC50 values were computed. The best-fit LC50 values, found to be significantly different (alpha < 0.0001), were 17.70 mg/mL and 56.04 mg/mL for C. citratus and O. gratissimum, respectively, suggesting that C. citratus is three times more potent than O. gratissimum. Phytochemical analysis of C. citratus indicated the presence of alkaloids, tannins, steroids, saponins, terpenoids and flavonoids. Cymbopogon citratus could be useful as an anthelmintic phytomedicine against livestock parasitic helminths. Keywords: Anthelmintic; Haemonchus placei; Motility assay; Ocimum gratissimum; Cymbopogon citratus
... (Besier, 2008). The available anthelmintics against gastrointestinal nematode are limited to three old classes which are the narrow spectrum benzimidazoles and broad-spectrum classes of imidazothiazoles and macrocyclic lactones (McKellar and Jackson, 2004), as well as three newer classes of broad-spectrum anthelminthics namely the aminoacetonitrile derivatives (AADs), spiroindols and cyclodepsipeptides (Epe and Kaminsky, 2013). ...
Thesis
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Gastrointestinal nematode infection is one of the major diseases affecting sheep and goats but most of the studies have focused on sheep. As a highly productive meat breed of goats, it is important to study the response of Boer breed to gastrointestinal nematode infection. The aim of this study was to investigate the interaction between Boer goats and their gastrointestinal nematodes by evaluating the phenotypic (faecal egg counts (FEC), IgA, packed cell volume (PCV), peripheral eosinophil counts and bodyweight) and parasitological (nematode number, length and index) variables following natural and deliberate co-infections that were dominated by Teladorsagia circumcincta and Haemonchus contortus, respectively. This study also aimed to estimate the repeatability, which provides an upper limit on heritability, and heritability of phenotypic variables among Boer goats, in particular the FEC as this is an important marker of resistance to gastrointestinal nematode infection. The study on natural infection was conducted in a farm in England with a semi-intensive grazing system whereas a deliberate infection study was conducted in a farm in Malaysia with an intensive management system. The FEC was confirmed to follow a zero-inflated Poisson distribution after comparing the observed and predicted zeroes in a Poisson regression. Mixed model repeated measures analysis that was conducted in a Bayesian framework was then used to analyse the phenotypic data. The findings from the studies of the phenotypic variables showed that the repeatability was moderate for FEC and PCV but relatively high for IgA activity and peripheral eosinophil counts and decreased significantly as the interval between sampling increased. The repeated measures models showed that FEC variation among Boer goats was affected by eosinophilia through time with the presence of an interaction with IgA responses, but that FEC was not heritable among Boer goats. The bodyweight of Boer goats was shown to be highly heritable despite them being infected with gastrointestinal nematodes. Additionally, the unaffected PCV levels and the increase in bodyweight over the course of infection suggest that Boer goats may be relatively resilient to gastrointestinal nematode infection. Multiple linear regression analyses of the mean phenotypic variables and the parasitological variables measured at necropsy suggested that H. contortus and Trichostrongylus colubriformis affected each other during co-infection. Shorter T. colubriformis was associated with greater H. contortus index and number whereas longer T. colubriformis was associated with a reduction in H. contortus number. Additionally, increased in IgA activity was associated with increased H. contortus length but a reduction in T. colubriformis index during co-infection. Together the findings show that eosinophils and IgA do play a role in the response of goats to gastrointestinal nematode infection, but the effects are less pronounced than in sheep. Moreover, the finding of a very low heritability of FEC is in contrast to findings in sheep. Most of the findings also suggest that the Boer breed is relatively resilient to infection but further work is needed to confirm whether these finding might be due to low infection doses. In conclusion, this study has expanded knowledge of the host-parasite relationship in goats as well as demonstrating interspecific nematode interactions between H. contortus and T. colubriformis, which commonly co-infect goats under natural conditions. However, future studies that overcome the limitations in the present study are needed to confirm the resistance status of Boer goats against these nematode species.
... Strategies to manage anthelmintic resistance should centre on refugia-based treatment schedules and the use of effective anthelmintics (Besier et al., 2016;Dobson et al., 2011). Although biological control and vaccination (for H. contortus) might have significant potential, parasite control programs still rely heavily on effective anthelmintic treatment (Besier et al., 2016;Epe and Kaminsky, 2013;Geary et al., 2015;Sargison, 2012). Currently, anthelmintics applied in the veterinary field include: the benzimidazoles, imidazothiazoles, macrocyclic lactones, monepantel and derquantel (reviewed by Besier et al., 2016;Harder, 2016;Kotze and Prichard, 2016;McKellar and Jackson, 2004;Sargison, 2012). ...
Chapter
Parasitic roundworms (nematodes) cause substantial morbidity and mortality in animals worldwide. Anthelmintic treatment is central to controlling these worms, but widespread resistance to most of the commercially available anthelmintics for veterinary and agricultural use is compromising control, such that there is an urgency to discover new and effective drugs. The purpose of this article is to review information on parasitic nematodes, the treatment and control of parasitic nematode infections and aspects of discovering new anthelmintics in the context of anthelmintic resistance problems, and then to discuss some progress that our group has made in identifying selected compounds with activity against nematodes. The focus of our recent work has been on discovering new chemical entities and known drugs with anthelmintic activities against Haemonchus contortus as well as other socioeconomically important parasitic nematodes for subsequent development. Using whole worm-based phenotypic assays, we have been screening compound collections obtained via product-development-partnerships and/or collaborators, and active compounds have been assessed for their potential as anthelmintic candidates. Following the screening of 15,333 chemicals from five distinct compound collections against H. contortus, we have discovered one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 tetrahydroquinoxaline analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro. Some of these 20 ‘hit’ compounds have selectivity against H. contortus in vitro when compared to particular human cell lines. In our opinion, some of these compounds could represent starting points for ‘lead’ development. Accordingly, the next research steps to be pursued include: (i) chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on a range of other parasitic nematodes, such as strongyloids, ascaridoids, enoplids and filarioids; (iii) detailed investigations of the absorption, distribution, metabolism, excretion and toxicity (ADMET) of optimised chemicals with broad nematocidal or nematostatic activity; and (iv) establishment of the modes of action of lead candidates.
... Research has shown that abamectin and avermectin have very similar biological and toxicological properties (Campbell 1989;Halley et al. 1993). Prior to use as a pesticide in agriculture farms, abamectin was used for the treatment and control of gastrointestinal nematodes as well as to control endo-and ecto-parasite infections in small ruminants (McKeller 1997;Chandrawathani and Nurul Aini 2012;Epe and Kaminsky 2013). Currently, abamectin is registered (RI. ...
Article
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Biological and behavioral responses of the tropical earthworm Perionyx excavatus towards different concentrations of abamectin were evaluated. Abamectin significantly reduced the biomass and reproduction (cocoon production) of P. excavatus as well as inducing histopathological alterations in the cuticle. Biomass loss was recorded in P. excavatus exposed to abamectin at a concentration as low as 0.1 mg active ingredient (a.i.) kg⁻¹, while atrophy, another physiological response, was observed at an abamectin concentration of 0.21 μg cm⁻² in a filter paper test. Cocoon production was significantly reduced in the presence of abamectin, and no cocoons were produced at doses of 20 mg a.i. kg⁻¹ or higher, while abamectin at 50 mg a.i. kg⁻¹ induced extreme pathology, characterized by the loss of the integrity of the whole body wall and intestine of P. excavatus. Histopathological alterations can be used as a biomarker to evaluate the toxicological impact of exposure to abamectin.
... The control of these nematodes has predominantly relied on the use of anthelmintic drugs, but the excessive and uncontrolled use of such drugs has led to widespread resistance in these nematodes to most anthelmintic classes [2], thus seriously compromising the control of parasites in many countries. Although the development of the compounds monepantel and derquantel (2-deoxyparaherquamide) [3][4][5] has provided some optimism about commercialising new classes of nematocides, success in bringing new anthelmintics to market has been limited over the last years. ...
Article
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Background Natural compounds from plants are known to provide a source of anthelmintic molecules. In previous studies, we have shown that plant extracts from the plant Picria fel-terrae Lour. and particular fractions thereof have activity against the free-living nematode Caenorhabditis elegans, causing quite pronounced stress responses in this nematode. We have also shown that a fraction, designated Pf-fraction 5, derived from this plant has a substantial adverse effect on this worm; however, nothing is known about the molecular processes affected in the worm. In the present study, we explored this aspect. Results Key biological processes linked to upregulated genes (n = 214) included ‘response to endoplasmic reticulum stress’ and ‘lipid metabolism’, and processes representing downregulated genes (n = 357) included ‘DNA-conformation change’ and ‘cellular lipid metabolism’. Conclusions Exposure of C. elegans to Pf-fraction 5 induces significant changes in the transcriptome. Gene ontology analysis suggests that Pf-fraction 5 induces endoplasmic reticulum and mitochondrial stress, and the changes in gene expression are either a direct or indirect consequence of this. Further work is required to assess specific responses to sub-fractions of Pf-fraction 5 in time-course experiments in C. elegans, to define the chemical(s) with potent anthelmintic properties, to attempt to unravel their mode(s) of action and to assess their selectivity against nematodes. Electronic supplementary material The online version of this article (10.1186/s13071-019-3429-4) contains supplementary material, which is available to authorized users.
... Helminth ion channels are outstanding targets for anthelmintic drugs. Anthelmintics known to act at least in part on parasite ion channels include ivermectin and other macrocyclic lactones, pyrantel, levamisole, monepantel, emodepside, piperazine, derquantel, tribendimidine, and likely PZQ (Epe and Kaminsky, 2013;Greenberg, 2014;Wolstenholme, 2011). No other class of parasite molecules is targeted nearly as extensively by current anthelmintics. ...
Article
Ion channels are membrane protein complexes that underlie electrical excitability in cells, allowing ions to diffuse through cell membranes in a regulated fashion. They are essential for normal functioning of the neuromusculature and other tissues. Ion channels are also validated targets for many current anthelmintics, yet the properties of only a small subset of ion channels in parasitic helminths have been explored in any detail. Transient receptor potential (TRP) channels comprise a widely diverse superfamily of ion channels with important roles in sensory signaling, regulation of ion homeostasis, organellar trafficking, and other functions. There are several subtypes of TRP channels, including TRPA1 and TRPV1 channels, both of which are involved in, among other functions, sensory, nociceptive, and inflammatory signaling in mammals. Several lines of evidence indicate that TRPA1-like channels in schistosomes exhibit pharmacological sensitivities that differ from their mammalian counterparts and that may signify unique physiological properties as well. Thus, in addition to responding to TRPA1 modulators, schistosome TRPA1-like channels also respond to compounds that in other organisms modulate TRPV1 channels. Notably, TRPV channel genes are not found in schistosome genomes. Here, we review the evidence leading to these conclusions and examine potential implications. We also discuss recent results showing that praziquantel, the current drug of choice against schistosomiasis, selectively targets host TRP channels in addition to its likely primary targets in the parasite. The results we discuss add weight to the notion that schistosome TRP channels are worthy of investigation as candidate therapeutic targets.
... It may be only a matter of time before this phenomenon becomes common in parasites of humans (Bachaya et al., 2009;Kaewintajuk et al., 2010;Taman and Azab, 2014;Geurden et al., 2015;Laing et al., 2016). Thus, the need for new anthelmintic compounds with novel mechanisms of action is clear (Epe and Kaminsky, 2013). ...
Article
Parasitic helminths continue to pose problems in human and veterinary medicine, as well as in agriculture. Resistance to current anthelmintics has prompted the search for new drugs. Anthelmintic metabolites from medicinal plants could be good anthelmintic drug candidates. However, the compounds active against nematodes have not been identified in most medicinal plants with anthelmintic activity. In this study, we aimed to identify the active compounds against helminths in Warburgia ugandensis Sprague subspecies ugandensis (Canellaceae) and study the underlying mechanism of action. A bioassay-guided isolation of anthelmintic compounds from the plant was performed using a Caenorhabditis elegans test model with a WMicrotracker instrument to monitor motility. Three active compounds were purified and identified by nuclear magnetic resonance and high resolution MS: warburganal (IC50: 28.2 ± 8.6 μM), polygodial (IC50: 13.1 ± 5.3 μM) and alpha-linolenic acid (ALA, IC50: 70.1 ± 17.5 μM). A checkerboard assay for warburganal and ALA as well as polygodial and ALA showed a fractional inhibitory concentration index of 0.41 and 0.37, respectively, suggesting that polygodial and ALA, as well as warburganal and ALA, have a synergistic effect against nematodes. A preliminary structure-activity relationship study for polygodial showed that the α,β-unsaturated 1,4-dialdehyde structural motif is essential for the potent activity. None of a panel of C. elegans mutant strains, resistant against major anthelmintic drug classes, showed significant resistance to polygodial, implying that polygodial may block C. elegans motility through a mechanism which differs from that of currently marketed drugs. Further measurements showed that polygodial inhibits mitochondrial ATP synthesis of C. elegans in a dose-dependent manner (IC50: 1.8 ± 1.0 μM). Therefore, we believe that the underlying mechanism of action of polygodial is probably inhibition of mitochondrial ATP synthesis. In conclusion, polygodial could be a promising anthelmintic drug candidate worth considering for further development.
... Emodepside is a semisynthetic derivative of the fermentation product PF1022A from the fungus Mycelia sterilia (Epe and Kaminsky, 2013). It is effective against a wide range of intestinal nematodes and lungworms and is licensed for use in cats. ...
Article
The global burden of ectoparasitic infestations is exacerbated by the lack of licensed vaccines, making safe and effective parasiticide drugs vital to their prevention and treatment. The last two decades in the companion animal parasiticides market has brought a welcome surge in the number of new antiparasitic agents. However, this requires veterinary prescribers to be much more knowledgeable about drug mode of action, indications, adverse reactions, and the potential for drug–drug interactions. Most antiparasitic drugs have an acceptable safety margin, however some are associated with clinically significant side effects or drug–drug interactions. The risk for these side effects can be increased when drugs are used in combination, and by concurrent medications prescribed for preexisting conditions. This article describes the risk of acute adverse reactions associated with treatment with antiparasitic drugs and highlights the current safety warnings regarding concurrent use of some drugs.
... Emodepside is a semisynthetic derivative of the fermentation product PF1022A from the fungus Mycelia sterilia (Epe and Kaminsky, 2013). It is effective against a wide range of intestinal nematodes and lungworms and is licensed for use in cats. ...
Article
The global burden of ectoparasitic infestations is exacerbated by the lack of licensed vaccines, making safe and effective parasiticide drugs vital to their prevention and treatment. The last two decades in the companion animal parasiticides market has brought a welcome surge in the number of new antiparasitic agents. However, this requires veterinary prescribers to be much more knowledgeable about drug mode of action, indications, adverse reactions, and the potential for drug-drug interactions. Most antiparasitic drugs have an acceptable safety margin, however some are associated with clinically significant side effects or drug-drug interactions. The risk for these side effects can be increased when drugs are used in combination and by concurrent medications prescribed for preexisting conditions. This article describes the risk of acute adverse reactions associated with treatment with antiparasitic drugs and highlights the current safety warnings regarding concurrent use of some drugs.
... In particular, anthelmintic resistance (AR) of cyathostomine populations to BZs is widespread [35][36][37][38][39][40], whilst resistance to PYR is common in some regions [37][38][39][41][42][43]. Therefore, given that none of the novel anthelmintics used in other veterinary species developed over the last decade are licenced for use in horses [44], current deworming programs aimed to control cyathostomine infections rely upon ML compounds. Amongst these, IVM and MOX are used interchangeably; nevertheless, the relative high cost of MOX compared to IVM [45], as well as ongoing efforts to preserve its efficacy against encysted larvae (by avoiding its excessive use) [36,46], make IVM the most widely used anthelmintic against cyathostomine infections. ...
Article
Background: In spite of the emergence of populations of drug-resistant cyathostomins worldwide, little is known of parasite species responsible for 'early egg shedding' in cohorts of horses subjected to treatment with widely used anthelmintics (e.g. ivermectin [IVM]). In this study, we determined the cyathostomin egg reappearance period (ERP) after IVM treatment of a cohort of yearlings from a large Thoroughbred (TB) stud farm in the United Kingdom, and identified species of IVM-'resistant' cyathostomins using a combination of fundamental parasitology techniques coupled with advanced molecular tools. Methods: Individual faecal samples were collected from TB yearlings with cyathostomin infection prior to IVM treatment, as well as at 2, 14, 21, 28, 35, 42 and 49 days posttreatment. Faecal egg counts (FEC) were performed for each individual sample for determination of ERPs. In addition, individual larval cultures were performed and representative numbers of third stage larvae (L3s) harvested from each culture were subjected to molecular species identification via PCR-Reverse Line Blot (RLB). Results: Prior to IVM treatment, 11 cyathostomin species were detected in faecal samples from TB horses enrolled in this study, i.e. Cyathostomum (Cya.) catinatum, Cylicostephanus (Cys.) longibursatus, Cys. goldi, Cylicocyclus (Cyc.) nassatus, Cys. calicatus, Cya, pateratum, Cyc. radiatus, Paraposteriostomum mettami, Coronocyclus (Cor.) labratus, Cyc. insigne and Cyc. radiatus variant A. Of these, eggs of Cya. catinatum, Cys. longibursatus, Cyc. nassatus and Cyc. radiatus could be detected at 28 days post-treatment, while from day 42 onwards, cyathostomin species composition reflected data obtained pre-IVM treatment, with the exception of eggs of Cor. labratus and Cyc. insigne that could no longer be detected post-IVM administration. Conclusions: This study provides valuable data on the occurrence of IVM-resistance in cyathostomins in the UK. Nevertheless, further investigations are needed to shed light on the prevalence and incidence of drug-resistance in this country as well as other areas of the world where equine trade is substantial.
... Atovaquone is used in the treatment of human malaria as well as human babesiosis and human toxoplasmosis (CDC 2016) caused by two related parasites, Babesia and Toxoplasma, respectively, belonging to the same phylum Apicomplexa. Albendazole, ivermectin, pyrantel pamoate, and praziquantel are all used indifferently on numerous species of helminth affecting humans and/or animals (Olliaro et al. 2011;Epe and Kaminsky 2013;CDC 2016) (Table 9.3). In the same way, research into new antiparasitic compounds explores the biological and biochemical similarities between human/animal affecting, or related parasite species. ...
Chapter
Parasitic diseases remain a major burden on global human and veterinary health. They affect more than two billion people worldwide causing considerable morbidity and mortality and are a major constraint on livestock production, especially in the world’s poorest communities. The immense suffering caused by these illnesses and the consequential loss of productivity is a major drain on the limited resources of the populations in which they occur. Most modern and effective drugs for parasitic diseases present no financial viability for the pharmaceutical industry since affected people have limited financial resources. Although financial return on investment is insufficient for drug discovery process and development, there is a constant desperate need for new chemical entities presenting new mechanisms of action. Higher plants, marine organisms, and microorganisms provide immense opportunities for the discovery of new drugs and drug leads. The screening of these natural sources thus remains one of the most attractive routes to discovering and developing new drugs. This article reviews the importance of natural products as a source of antiparasitic drugs and discusses some of the research challenges.
... It must be recognized that several new anthelmintic classes have been brought to market for veterinary applications in the fairly recent past, including cyclic depsipeptides (emodepside), amino-acetonitriles (monepantel) and paraherquamides (derquantel), with others presumably in various stages of development (Epe and Kaminsky, 2013). Too few data are available to allow an in-depth analysis of why mechanism-based approaches have not yet succeeded in parasitology (Geary, 2012;Crowther et al. 2014). ...
Article
Helminth infections have large negative impacts on production efficiency in ruminant farming systems worldwide, and their effective management is essential if livestock production is to increase to meet future human needs for dietary protein. The control of helminths relies heavily on routine use of chemotherapeutics, but this approach is unsustainable as resistance to anthelmintic drugs is widespread and increasing. At the same time, infection patterns are being altered by changes in climate, land-use and farming practices. Future farms will need to adopt more efficient, robust and sustainable control methods, integrating ongoing scientific advances. Here, we present a vision of helminth control in farmed ruminants by 2030, bringing to bear progress in: (1) diagnostic tools, (2) innovative control approaches based on vaccines and selective breeding, (3) anthelmintics, by sustainable use of existing products and potentially new compounds, and (4) rational integration of future control practices. In this review, we identify the technical advances that we believe will place new tools in the hands of animal health decision makers in 2030, to enhance their options for control and allow them to achieve a more integrated and sustainable approach to helminth control in support of animal welfare and production.
... In particular, anthelmintic resistance (AR) of cyathostomine populations to BZs is widespread [35][36][37][38][39][40], whilst resistance to PYR is common in some regions [37][38][39][41][42][43]. Therefore, given that none of the novel anthelmintics used in other veterinary species developed over the last decade are licenced for use in horses [44], current deworming programs aimed to control cyathostomine infections rely upon ML compounds. Amongst these, IVM and MOX are used interchangeably; nevertheless, the relative high cost of MOX compared to IVM [45], as well as ongoing efforts to preserve its efficacy against encysted larvae (by avoiding its excessive use) [36,46], make IVM the most widely used anthelmintic against cyathostomine infections. ...
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Background: In spite of the emergence of populations of drug-resistant cyathostomines worldwide, little is known of parasite species responsible for 'early egg shedding' in cohorts of horses subjected to treatment with widely used anthelmintics, e.g. ivermectin (IVM). In this study, we determined the cyathostomine egg reappearance period (ERP) after IVM treatment in a cohort of yearlings from a large Thoroughbred (TB) stud farm in the United Kingdom, and identified species of cyathostomines with reduced ERP using a combination of fundamental parasitology techniques coupled with advanced molecular tools. Methods: Individual faecal samples were collected from TB yearlings with cyathostomine infection prior to IVM treatment, as well as at 14, 21, 28, 35, 42 and 49 days post-treatment. Faecal egg counts (FEC) were performed for each individual sample for determination of ERPs. In addition, individual larval cultures were performed and representative numbers of third-stage larvae (L3s) harvested from each culture were subjected to molecular species identification via PCR-Reverse Line Blot (RLB). Results: Prior to IVM treatment, 11 cyathostomine species were detected in faecal samples from TB horses enrolled in this study, i.e. Cyathostomum catinatum, Cylicostephanus longibursatus, Cylicostephanus goldi, Cylicocyclus nassatus, Cylicostephanus calicatus, Cyathostomum pateratum, Cylicocyclus radiatus, Paraposteriostomum mettami, Coronocyclus labratus, Cylicocyclus insigne and Cylicocyclus radiatus variant A. Of these, eggs of Cya. catinatum, Cys. longibursatus, Cyc. nassatus and Cyc. radiatus could be detected at 28 days post-treatment, while from day 42 onwards, cyathostomine species composition reflected data obtained pre-IVM treatment, with the exception of eggs of Cor. labratus and Cyc. insigne which could no longer be detected post-IVM administration. Conclusions: This study provides valuable data on the occurrence of IVM-resistance in cyathostomines in the UK. Nevertheless, further investigations are needed to shed light on the prevalence and incidence of drug-resistance in this country, as well as other areas of the world where equine trade is substantial.
... A disseminação da resistência anti-helmíntica e o longo tempo necessário para o desenvolvimento de uma nova molécula com ação antiparasitária [22] impuseram a busca por alternativas de controle sustentável e ecologicamente correto [24]. Estas alternativas devem ser empregadas combinando os três princípios básicos: 1) gestão dos sistemas de pastoreio; 2) estimulação da resposta do hospedeiro; 3) modulação da biologia dos nematoides [37]. ...
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Background: Gastrointestinal nematodes are one of the major health and economic problem of sheep and goats in the world. The control of these nematodes is carried out conventionally with synthetic anthelminths, which favored the selection of gastrointestinal nematode (GIN) populations multiresistant to anthelmintics. The emergence of anthelmintic resistance has stimulated the search for new alternatives to control small ruminant GIN, standing out the use of plants and their bioactives compounds, such as essential oils (EO). The objective of this review was to present the main characteristics and anthelmintic activity of EO, their isolated compounds and drug delivery systems in the control of GIN. Review: Essential oils are a complex blend of bioactive compounds with volatile, lipophilic, usually odoriferous and liquid substances. EO are composed of terpenes, terpenoids, aromatic and aliphatic constituents. EO has various pharmacological activities of interest in preventive veterinary medicine such as antibacterials, antifungals, anticoccicids, insecticides and anthelmintics. In vitro and in vivo tests are used to validate the anthelmintic activity of EO on GIN. In vitro tests are low cost screening tests that allow the evaluation of the anthelmintic activity of a large amount of bioactive compounds on eggs, first (L1) and third stage larvae (L3), and adult nematodes. The antiparasitic effect of EO is related to its main compound or to the interaction of the compounds. These bioactive compounds penetrate the cuticle of the nematodes by transcuticular diffusion, altering the mechanisms of locomotion, besides causing cuticular lesions. Following in vitro evaluation, the acute and sub-chronic toxicity test should be performed to assess the toxicity of the bioactive compounds and to define the dose to be used in in vivo tests. In vivo tests are more reliable because the anthelmintic effectiveness of bioactive compounds is evaluated after the metabolization process. The metabolization process of the bioactive compounds can generate metabolites that exhibit or not anthelmintic effectiveness. The in vivo tests assessing the anthelmintic effectiveness of bioactive compounds in sheep and goats are the fecal egg count reduction test and the controlled test. OE promoted reduction of egg elimination in faeces which may be related to cuticular and reproductive alterations in GIN, and reduction of parasite burden in in vivo tests. Due to the promising results obtained with OE in the in vivo tests, interest has been aroused in using nanotechnology as an alternative to increase the bioavailability of OE and consequently, potentializing its anthelmintic effect, reducing the dose and toxicity of the biocompounds. In addition to nanotechnology, the isolation and chemical modification of compounds isolated from OE have been employed to obtain new molecules with anthelmintic action and understand the mechanism of action of EO on the small ruminant GIN. Conclusion: The use of EO and their compound bioactive in the control of resistant populations of GIN is a promising alternative. The adoption of strategies in which natural products can replace synthetic anthelmintics, such as in dry periods and use synthetic anthelmintics in the rainy season when the population in refugia in the pasture is high, thus reducing the dissemination of GIN resistant populations. As perspective, the evaluation of pharmacokinetics and pharmacodynamics of these natural products should be performed so that one defines treatment protocols that optimize the anthelmintic effect.
... Given the substantial problems linked to anthelmintic resistance in parasitic worms of livestock animals, a continued effort is needed to search for new and effective chemicals for development and commercialisation, particularly if they have new modes of action compared with existing drugs (Epe and Kaminsky, 2013). There has been a renewed interest in pursuing natural products for drug discovery (Shen, 2015) because of the biologically relevant chemical diversity of such products and because they are aligned with Nature's need to develop a "chemical warfare" arsenal (Baell, 2016). ...
Article
The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n = 400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to mammals/vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes and to assess its potential as an anthelmintic candidate.
... The widespread resistance of parasitic worms of livestock animals to commonly used anthelmintics necessitates continued efforts to discover new effective chemicals for subsequent commercial development, particularly those with new modes of action to limit cross-resistance (1). Natural products have enormous chemical and structural diversity that is unmatched by synthetic sets of small molecules (2). ...
Article
As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mito-ribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
Article
Monepantel (MNP) is a new class of aminoacetonitrile derivative antiparasitic drug and mainly metabolizes as monepantel sulfone in vivo. This study aimed at developing a novel monepantel sulfone (MNPS) detection method combining indirect competitive enzyme-linked immunosorbent assay (icELISA) and immunomagnetic separation. An easy-synthesized hapten was designed based on the partial structure of MNPS. A monoclonal antibody was obtained by immunizing mice, and applied to icELISA. The half inhibition concentration (IC50) was 1.36 ng/mL, the limit of detection (LOD) was 0.25 μg/L. The average recoveries of the icELISA ranged from 89.5% to 114.5% with the coefficient of variation lower than 13.2%. In summary, a rapid and reliable icELISA was developed for detecting MNPS in milk samples for the first time.
Chapter
The structure and function of the caprine digestive system follow the basic ruminant design and closely resemble those of sheep. This chapter discusses the major diseases that affect primarily the digestive system. Abdominal pain in goats may be manifested by depression, restlessness, bleating, teeth grinding, reluctance to move, increased shallow respiration, increased heart rate, tenesmus, or an abnormal posture with an arched back and tucked‐up abdomen. Rinderpest, or cattle plague, is best known as a devastating disease of cattle caused by a morbillivirus in the family Paramyxoviridae. Bluetongue is an infectious, non‐contagious, arthropod‐borne, viral disease of ruminants. Paramphistomes are trematode parasites commonly referred to as rumen flukes, stomach flukes, or conical flukes. Intestinal tapeworms occur in goats throughout the world. Ruminal tympany, or bloat, is less common in goats than in cattle and sheep.
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Onchocerciasis affects predominantly rural communities in Africa, and with small foci in South America and the Yemen. The disease is a major cause of blindness and other significant morbidity and mortality. Control programs have achieved a major impact on the incidence and prevalence of onchocerciasis by interrupting transmission with vector control programs, and treatment with mass drug administration using the microfilaricide ivermectin. Over the last few decades, several microfilaricides have been developed. This initially included diethylcarbamazine, which had significant side effects and is no longer used as such. Ivermectin which is a safe and highly effective microfilaricide and moxidectin which is a longer acting microfilaricide are presently recognized therapies. Suramin was the first effective macrofilaricide but was prohibitively toxic. Certain antibiotics including doxycycline can help eliminate adult worms by targeting its endosymbiont bacteria, Wolbachia pipientis. However, the dosing regimens may make this difficult to use as part of a mass disease control program in endemic areas. It is now widely recognized that treatments that are able to kill or permanently sterilize adult filarial worms should help achieve the elimination of this disease. We summarize in detail the historic drug development in onchocerciasis, including prospective future candidate drugs.
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Parasitic nematodes devastate human and animal health. The limited number of anthelmintics available is concerning, especially because of increasing drug resistance. Anthelmintics are commonly derived from natural products, e.g. fungi and plants. This investigation aimed to develop a high-throughput whole organism screening method based on a motility assay using the wMicroTracker system. Anthelmintic activity of extracts from Hawaiian fungi was screened against third-stage larvae of the parasitic nematode Angiostrongylus cantonensis , categorized according to the degree of motility reduction. Of the 108 crude samples and fractionated products, 48 showed some level of activity, with 13 reducing motility to 0–25% of the maximum exhibited, including two pure compounds, emethacin B and epicoccin E, neither previously known to exhibit anthelmintic properties. The process of bioassay-guided fractionation is illustrated in detail based on analysis of one of the crude extracts, which led to isolation of lamellicolic anhydride, a compound with moderate activity. This study validates the wMicroTracker system as an economical and high-throughput option for testing large suites of natural products against A. cantonensis , adds to the short list of diverse parasites for which it has been validated and highlights the value of A. cantonensis and Hawaiian fungi for discovery of new anthelmintics.
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Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1 , a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1 , but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies when parasites are underdosed. We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across natural nematode populations. Graphical abstract Highlights Emodepside responses vary across the C. elegans species. Wild strains of C. elegans model natural differences in parasite emodepside responses. Variation in the emodepside target slo-1 and other loci correlate with resistance. Low doses of emodepside cause a hormetic effect on offspring production.
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Background: The use of the edible biomass of Dichrostachys cinerea constitutes an alternative for ruminants feeding and for the parasites control in such animals. With the present research the "in vitro" anthelminthic activity of aqueous extracts obtained from pods, shoots and leaves of mature plants were evaluated. Methods. From the botanic materials collected mother solutions were obtained three, and from these the aqueous extracts by infusion, decoction and maceration were prepared which were diluted at 10% for infusion and decoction, and at 10, 15 and 20% for maceration, resulting in 15 treatments. In addition, four controls, two positives and two negatives, were used. The earth worm was used as biological model. For each treatment a Petri plate was used in which 10 ml of the extract in question and six worms ware added. The time, in minutes, of occurrence of paralysis and death of the worms was measured. Results. The anthelminthic effect of the infusion and decoction at 10% didn't show significant differences for the death time of the earth worms. The obtaining of the extracts by maceration enabled a bigger extraction of secondary metabolites, which are responsible for the anthelminthic activity demonstrated in this study. Conclusions. All the extracts showed anthelminthic activity. The aqueous extract obtained by maceration and diluted at 20% was the most effective for the three studied vegetal materials. Keywords: helminthes, leaves, kakada, pods, shoots (Source: AIMS)
Article
Ethnopharmacological relevance The leaf of Sarcocephalus latifolius is known to be used traditionally by the Fulanis in Nigeria to deworm animals. As helminthosis remains a major constraint to profitable livestock production worldwide, a precarious situation aggravated by the advent of resistant parasites, the discovery of new anthelmintics is a priority, necessitating exploration of medicinal plants for their anthelmintic principles. Aim of the study: To identify and characterise compounds with anthelmintic activity from the leaf of Sarcocephalus latifolius. Materials and methods Powdered S. latifolius leaf was extracted successively with n-hexane, chloroform and acetone. The dried extracts were evaluated for anthelmintic activity against Haemonchus placei adult worms, and the most active extract was subjected to bioassay-guided chromatographic separations. The isolated compounds were evaluated for cytotoxicity against the mammalian HeLa and MC3T3-E1 cell lines, using alamar blue and CellTitreGloTM to quantify cell viability. LC50 values were computed from the in vitro anthelmintic activity data by fitting to a non-linear regression equation (variable slope). Isolated compounds were characterized using spectroscopic and mass spectrometric analyses. Results Anthelmintic activity LC50 values for n-hexane, chloroform and acetone extracts were 47.85, 35.76 and 5.72 (mg/mL), respectively. Chromatographic separation of acetone extract afforded two bioactive epimers, identified as strictosamide (LC50 14.7 mg/mL) and vincosamide (LC50 12.8 mg/mL). Cytotoxicity evaluation showed that, below 200 μg/mL (400 μM), neither compound was toxic to the Hela or MC3T3-E1 cells. Conclusion Strictosamide and vincosamide could serve as novel scaffolds for the development of anthelmintic derivatives with improved potency and helminth selectivity.
Article
Background: literature survey has pointed out that Benzimidazoles represent an interesting class of anthelmintics of which several potent members were developed. Objective: Benzimidazoles hybridized with pharmacophoric moieties possessing anthelmintic activity were designed, synthesized to be evaluated against cercaria. Methods: Structural modification was achieved through 2- and 5-positions. Moreover, in vitro cercarial assay was adopted to evaluate target compounds. Results: Biological screening revealed that compound 3h showed significant activity with survival index of 35% at a 100 µg/mL concentration. Whereas, compounds 3a and 3c showed moderate activity, the rest of tested compounds exhibited low activity. Conclusion: The current study evidenced that the new hybrids "benzimidazole-thiophen-aryl" are successful as cercacidal agents. Further studies of this novel tri-ring systems are suggested on adult worms of S. Mansoni.
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Ion channels underlie electrical excitability in cells and are essential for a variety of functions, most notably neuromuscular and sensory activity. They are also validated targets for a preponderance of approved anthelmintic compounds. Transient receptor potential (TRP) channels constitute an ion channel superfamily whose members play important roles in sensory signaling, regulation of ion homeostasis, organellar trafficking, and other key cellular and organismal activities. Unlike most other ion channels, TRP channels are often polymodal, gated by a variety of mechanisms. Furthermore, TRP channels fall into several classes or subtypes based on sequence and structure. Until recently, there had been very little investigation of the properties and functions of TRP channels from parasitic helminths, including schistosomes, but that situation has changed in the past few years. Indeed, it is now clear that at least some schistosome TRP channels exhibit unusual pharmacological properties, and, intriguingly, both a mammalian and a schistosome TRP channel are activated by praziquantel, the current antischistosomal drug of choice. With the latest release of the Schistosoma mansoni genome database, several changes in predicted TRP channel sequences appeared, some of which were significant. This review updates and reassesses the TRP channel repertoire in S. mansoni, examines recent findings regarding these potential therapeutic targets, and provides guideposts for some of the physiological functions that may be mediated by these channels in schistosomes.
Chapter
This chapter provides pertinent information about common parasites that infect dogs and cats, including the patho physiology of the body system(s) affected by the parasite. Additionally, zoonotic potential is noted as well as the presence of parasite life cycle stages that abrogate susceptibility to antiparasitic drugs. To enhance the spectrum of activity and provide a one‐drug‐treats‐all solution, many manufacturers combine several drugs into one product that has activity against both internal and external parasites. The chapter lists the common formulations, their spectrum, and dosages. The chapter also provides a broad overview of treatment considerations for external parasites and compares treatment options across drug families. Traditionally, antiparasitic agents were organized by whether their action was directed against internal versus external parasites. However, many newer compounds are “endectocides,” which have activities against both internal and external parasites. The chapter provides information on the spectrum of commercial products.
Article
Anthelmintic drugs are used to control intestinal parasitic worms in animals worldwide. Although generally effective in managing animal health, such treatment can introduce anthelminthic compounds to the wider environment as active ingredients and metabolites are often excreted. This can have detrimental effects on non-target species, especially when drugs are used excessively. Here, we examine the effects that two environmentally-realistic concentrations of four anthelminthics have on the common earthworm Lumbricus terrestris (Linnaeus, 1758), a species with a cosmopolitan distribution and that is often vital in maintaining functional edaphic ecosystems. The drugs were ivermectin (0.502 and 2.511 mg kG ⁻¹ active ingredient), fenbendazole (0.309 and 1.547 mg kG ⁻¹ ), pyrantel (79.480 and 397.400 mg kG ⁻¹ ), and praziquantel (2.299 and 11.499 mg kG ⁻¹ ): these concentrations were typical of soils where pasture grazed by animals treated with anthelminthics. Both lethal effects (mortality) and sub-lethal effects (motility) were considered. Earthworms exposed to fenbendazole and praziquantel over a 12-week period experienced high mortality (55.0% and 32.5%, respectively). Mortality rates among earthworms exposed to pyrantel and ivermectin were much lower (2.5% and 7.5%, respectively). However, earthworms exposed to pyrantel and ivermectin suffered decreased motility (time to burrow into substrate when exposed to heat and light) relative to a control group. Burrowing times were up to 40% longer for pyrantyl-exposed earthworms and 28% longer for ivermectin-exposed earthworms. For both drugs, the magnitude of the effect increased as concentration increased; all differences were statistically significant. There was little effect of fenbendazole and praziquantel on motility. Based on this study, which is seemingly the first to examine effects of ivermectin/fenbendazole on earthworm motility and the first to consider any effects of praziquantel/pyrantel, we conclude that environmentally-realistic concentrations of all four anthelmintics have sub-lethal (pyrantel and ivermectin) or lethal (fenbendazole and praziquantel) effects on a vital keystone species. Methods to reduce carry-over effects in ecologically-important, non-target, organisms should be urgently sought and care should be taken not to use anthelminthics routinely without first testing helminth burden to determine whether there is clinical need.
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Currently, the use of medicinal plants has become an alternative for treatment and control of diseases in both veterinary and human medicine. Recent studies have reported that secondary metabolites present in all plants have effects on production and animal health as they have bactericidal or bacteriostatic, anthelmintic (tannins and saponins), anticancer, antioxidant and immunostimulant (phenolic compounds, alkaloid saponins, and terpenes) effects; and for their content of secondary metabolites they have been proposed as an alternative in animal feed because can increase productive and reproductive parameters. The presence or absence of these effects depends on the kind of plant, the content of secondary metabolites, the kind of secondary metabolite and the quantity and the frequency in which they are consumed. The aim of the present review was to carry out a bibliography search of the main secondary metabolites of plants with antimicrobial and over gastrointestinal nematodes activity, reported in Veterinary Medicine
Chapter
Goats raised in pasture are inevitably infected by gastrointestinal nematodes, whatever the place and the climatic conditions. This parasitism results in production losses (growth or milk) and in some cases, in high mortality rates (with high parasite burden or in kids). For many years, these infections were controlled by conventional anthelmintics. Due to unsuitable usages (for example, high number of treatments or under-dosage), anthelmintic resistance has developed and is now very prevalent in goats as demonstrated by the numerous cases of simple or multiple anthelminthic resistance which have been reported throughout the world. Reports include resistance to the most recent anthelmintics, macrocyclic lactones and monepantel. Consequently, the way of managing gastrointestinal parasitism of goats has to move from anthelmintics alone to a more integrated management, including better use of anthelmintics, natural dewormers (nutraceuticals), enhancement of the immunity of the goats via alimentation or vaccination, selection of resistant goats or breeds and grazing management. The present chapter will give an overview of the situation regarding anthelmintic resistance in goats and integrated parasitism management.
Chapter
Livestock parasite resistance to anthelmintics remains one of the major limitations to ongoing animal health, welfare and productivity worldwide. Subsequent less-than-optimal parasite control can impose significant direct and indirect costs within all production and recreation livestock enterprises. This chapter briefly summarises the biology and epidemiology of the important nematode and trematode parasites of cattle, sheep and horses around the world. Then it details the application, including modes of action and specific mechanisms of resistance, of the key anthelmintic options to assist their control. The general principles regarding the development of anthelmintic resistance are discussed in light of an understanding to assist the slowing of worsening spread and to support effective and sustainable helminth control. There is also discussion of methods to detect, measure and monitor anthelmintic resistance.
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Nematode parasites infect humans and domestic animals; treatment and prophylaxis require anthelmintic drugs because vaccination and sanitation is limited. Emodepside is a more recently introduced cyclooctadepsipeptide drug that has actions against GI nematodes, lungworm, and microfilaria. It has a novel mode of action which breaks resistance to the classical anthelmintics (benzimidazoles, macrocyclic lactones and cholinergic agonists). Here we review studies on its mode of action which suggest that it acts to inhibit neuronal and muscle activity of nematodes by increasing the opening of calcium-activated potassium (SLO-1) channels.
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In order to provide a background to current concerns relative to the possible resistance of heartworms to macrocyclic lactones, this review summarizes various studies in which lack of efficacies (LOEs) have been observed in dogs on macrocyclic lactone preventives relative to the United States of America. Some of these studies have been published in the peer-reviewed literature, others have appeared in various reports to the Center for Veterinary Medicine (CVM) of the Food and Drug Administration (FDA) of the USA as New Animal Drug Application (NADA) summaries, and one appeared as a letter to US veterinarians. This review also discusses reports relating to the potential problem of heartworm resistance in microfilariae and third-stage larvae, as well as molecular markers associated with resistance to macrocyclic lactones within Dirofilaria immitis. As more work is being done in this area of great concern relative to the protection of dogs from infection using this class of preventives, it seems timely to summarize what is known about heartworms, their potential resistance to treatment, and the means of selecting for resistance genes in populations of this helminth in the laboratory and in the field.
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The cyclo-octapdepsipeptide anthelmintic emodepside exerts a profound paralysis on parasitic and free-living nematodes. The neuromuscular junction is a significant determinant of this effect. Pharmacological and electrophysiological analyses in the parasitic nematode Ascaris suum have resolved that emodepside elicits a hyperpolarisation of body wall muscle, which is dependent on extracellular calcium and the efflux of potassium ions. The molecular basis for emodepside's action has been investigated in forward genetic screens in the free-living nematode Caenorhabditis elegans. Two screens for emodepside resistance, totalling 20,000 genomes, identified several mutants of slo-1, which encodes a calcium-activated potassium channel homologous to mammalian BK channels. Slo-1 null mutants are more than 1000-fold less sensitive to emodepside than wild-type C. elegans and tissue-specific expression studies show emodepside acts on SLO-1 in neurons regulating feeding and motility as well as acting on SLO-1 in body wall muscle. These genetic data, combined with physiological measurements in C. elegans and the earlier physiological analyses on A. suum, define a pivotal role for SLO-1 in the mode of action of emodepside. Additional signalling pathways have emerged as determinants of emodepside's mode of action through biochemical and hypothesis-driven approaches. Mutant analyses of these pathways suggest a modulatory role for each of them in emodepside's mode of action; however, they impart much more modest changes in the sensitivity to emodepside than mutations in slo-1. Taken together these studies identify SLO-1 as the major determinant of emodepside's anthelmintic activity. Structural information on the BK channels has advanced significantly in the last 2 years. Therefore, we rationalise this possibility by suggesting a model that speculates on the nature of the emodepside pharmacophore within the calcium-activated potassium channels.
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Nematode parasites infect humans and domestic animals; treatment and prophylaxis require anthelmintic drugs because vaccination and sanitation is limited. Emodepside is a more recently introduced cyclooctadepsipeptide drug that has actions against GI nematodes, lungworm, and microfilaria. It has a novel mode of action which breaks resistance to the classical anthelmintics (benzimidazoles, macrocyclic lactones and cholinergic agonists). Here we review studies on its mode of action which suggest that it acts to inhibit neuronal and muscle activity of nematodes by increasing the opening of calcium-activated potassium (SLO-1) channels.
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Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%).
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Author Summary Increased use of anthelmintics has contributed to the emergence of drug-resistant nematodes, causing serious problems for more than one billion sheep worldwide. The last class of compounds indicated for livestock was introduced 28 years ago. Recently, however, Novartis AH developed a new anthelmintic active against drug-resistant nematodes of sheep, the amino-acetonitrile derivative (AAD) monepantel. We have previously indirectly shown that the AADs have a novel mode of action involving acetylcholine receptor subunits: the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus. To better understand the mode of action of the AADs, we performed comparative genomics of all ligand-gated ion channel genes from a range of organisms, including members from all nematode clades. We confirmed that MPTL-1 belongs to a unique, nematode-specific sub-family of receptor subunits. We also found that some nematode species lack ACR-23/MPTL-1 and predicted them to be monepantel insensitive. We challenged this hypothesis in a panel of drug tests: several species of Caenorhabditis nematodes equipped with ACR-23/MPTL-1-like receptor subunits were found susceptible to monepantel, whereas Pristionchus pacificus, closely related to these worms but lacking an ACR-23/MPTL-1 homolog, was tolerant. The parasitic nematode Strongyloides ratti, which has only a remote homolog of DES-2 and ACR-23/MPTL-1, was also tolerant to monepantel. This confirms our prediction and highlights how comparative genomic data can be used to predict a drug effect.
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Gastro-intestinal nematodes in ruminants, especially Haemonchus contortus, are a global threat to sheep and cattle farming. The emergence of drug resistance, and even multi-drug resistance to the currently available classes of broad spectrum anthelmintics, further stresses the need for new drugs active against gastro-intestinal nematodes. A novel chemical class of synthetic anthelmintics, the Amino-Acetonitrile Derivatives (AADs), was recently discovered and the drug candidate AAD-1566 (monepantel) was chosen for further development. Studies with Caenorhabditis elegans suggested that the AADs act via nicotinic acetylcholine receptors (nAChR) of the nematode-specific DEG-3 subfamily. Here we identify nAChR genes of the DEG-3 subfamily from H. contortus and investigate their role in AAD sensitivity. Using a novel in vitro selection procedure, mutant H. contortus populations of reduced sensitivity to AAD-1566 were obtained. Sequencing of full-length nAChR coding sequences from AAD-susceptible H. contortus and their AAD-1566-mutant progeny revealed 2 genes to be affected. In the gene monepantel-1 (Hco-mptl-1, formerly named Hc-acr-23H), a panel of mutations was observed exclusively in the AAD-mutant nematodes, including deletions at intron-exon boundaries that result in mis-spliced transcripts and premature stop codons. In the gene Hco-des-2H, the same 135 bp insertion in the 5' UTR created additional, out of frame start codons in 2 independent H. contortus AAD-mutants. Furthermore, the AAD mutants exhibited altered expression levels of the DEG-3 subfamily nAChR genes Hco-mptl-1, Hco-des-2H and Hco-deg-3H as quantified by real-time PCR. These results indicate that Hco-MPTL-1 and other nAChR subunits of the DEG-3 subfamily constitute a target for AAD action against H. contortus and that loss-of-function mutations in the corresponding genes may reduce the sensitivity to AADs.
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Tribendimidine is an anthelminthic drug with a broad spectrum of activity. In 2004 the drug was approved by Chinese authorities for human use. The efficacy of tribendimidine against soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) has been established, and new laboratory investigations point to activity against cestodes and Strongyloides ratti. In an open-label randomized trial, the safety and efficacy of a single oral dose of albendazole or tribendimidine (both drugs administered at 200 mg for 5- to 14-year-old children, and 400 mg for individuals > or = 15 years) against soil-transmitted helminths, Strongyloides stercoralis, and Taenia spp. were assessed in a village in Yunnan province, People's Republic of China. The analysis was on a per-protocol basis and the trial is registered with controlled-trials.com (number ISRCTN01779485). Both albendazole and tribendimidine were highly efficacious against A. lumbricoides and, moderately, against hookworm. The efficacy against T. trichiura was low. Among 57 individuals who received tribendimidine, the prevalence of S. stercoralis was reduced from 19.3% to 8.8% (observed cure rate 54.5%, p = 0.107), and that of Taenia spp. from 26.3% to 8.8% (observed cure rate 66.7%, p = 0.014). Similar prevalence reductions were noted among the 66 albendazole recipients. Taking into account "new" infections discovered at treatment evaluation, which were most likely missed pre-treatment due to the lack of sensitivity of available diagnostic approaches, the difference between the drug-specific net Taenia spp. cure rates was highly significant in favor of tribendimidine (p = 0.001). No significant adverse events of either drug were observed. Our results suggest that single-dose oral tribendimidine can be employed in settings with extensive intestinal polyparasitism, and its efficacy against A. lumbricoides and hookworm was confirmed. The promising results obtained with tribendimidine against S. stercoralis and Taenia spp. warrant further investigations. In a next step, multiple-dose schedules should be evaluated.
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Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK(B) values of the antagonists. The analysis was tested using Clark plots. The pK(B) values for paraherquamide were: nicotine, 5.86 +/- 0.14; levamisole, 6.61 +/- 0.19; pyrantel, 6.50 +/- 0.11; and bephenium, 6.75 +/- 0.15. The pK(B) of nicotine was significantly different from the pK(B) values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK(B) values for 2-deoxy-paraherquamide were: levamisole, 5.31 +/- 0.13; pyrantel, 5.63 +/- 0.10; and bephenium, 6.07 +/- 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK(B) values of levamisole and pyrantel were significantly different from the pK(B) of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.
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Pharmacological experiments on Ascaris suum have demonstrated the presence of three (N-, L-, and B-) subtypes of cholinergic receptor mediating contraction of body wall muscle in parasitic nematodes. In the present study, these ionotropic acetylcholine (ACh) receptors (nAChRs) were activated by levamisole and bephenium under patch-clamp conditions and competitively antagonized by paraherquamide and 2-desoxoparaherquamide. A number of recordings exhibited three separate current amplitude levels, indicating the presence of small, intermediate, and large conductance subtypes of receptor. The mean conductance of the small conductance subtype, G25, was 22 +/- 1 pS; the intermediate conductance channel, G35, was 33 +/- 1 pS; and the large conductance channel, G45, was 45 +/- 1 pS. The small channel was not antagonized significantly by paraherquamide and was identified as the N-subtype. The intermediate channel was preferentially activated by levamisole rather than bephenium and antagonized by paraherquamide: the intermediate channel was identified as the L-subtype. The large conductance channel was preferentially activated by bephenium, antagonized more by 2-desoxoparaherquamde than by paraherquamide and was identified as the B-subtype. These observations reveal that the three channel subtypes have different selectivity for cholinergic anthelmintics. The different selectivity of these compounds should be considered when dealing with drug resistant infections.
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Between 1960 and 1980, extraordinary success was achieved in anthelmintic development for animals. In these 20 years, drugs with diverse structure, novel activity and enviable safety were produced for a global livestock industry leading to the productivity gains needed to support a human population that grew by 1.5 billion during the same period. The following 20 years have been spent refining existing molecules with niche activity (parasite and host specificity), improving delivery systems and worrying about the inexorable spread of drug resistance. The challenge for the next 20 years will be to use the technologies available to design and produce new drugs and biological controls. Then, to use the lessons of the past to ensure that the new drugs enjoy a longer useful lifespan and contribute to an animal health industry (livestock and companion) which enriches the lives of a global population. Old and new veterinary anthelmintics comprise a very large field, which could not be comprehensively reviewed in a short article. The present mini-review focuses on major chemical discoveries, formulation developments, administration strategies and new products.
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Until recently, only three broad-spectrum classes of anthelmintics for the control of gastrointestinal nematodes of livestock were available: the benzimidazoles, the imidazothiazoles, and the macrocyclic lactones. In 2008, Novartis Animal Health reported the discovery of the amino-acetonitrile derivatives (AADs) as a potential new class of broad-spectrum anthelmintics for livestock. The objectives of the present chapter are to introduce the AADs, their discovery, their safety and efficacy profiles, the selection of monepantel as the first candidate for commercial use, and, finally, the investigation of the mode of action of this active ingredient.
Chapter
The frequent use of anthelmintics, particularly in geographic areas of intense parasite transmission, has led to the selection and spread of parasite strains that are resistant to them. Against that backdrop, Upjohn Animal Health (now Pfizer Animal Health) established a discovery program to identify compounds with novel modes of action and effective against several important nematode species, including strains resistant to the major classes of anthelmintics. This testing led to the discovery of 2-deoxy-paraherquamide (derquantel) – the first of the spiroindole class of anthelmintics with commercial utility. Derquantel was prepared semisynthetically by chemical reduction of paraherquamide, isolated from fermentation extracts of Penicillium simplicissimum. It was subsequently shown that derquantel is a nicotinic cholinergic antagonist. During clinical development, derquantel was combined with the macrocyclic lactone, abamectin. The combination of the new chemical with a second anthelmintic from a different chemical class in a single product (Startect®) provides a more complete spectrum of anthelmintic activity and efficacy against resistant strains. Additionally, the combination also offers a means of minimizing selection for resistance to derquantel through the use of abamectin with a second, distinct mode of action, thereby potentially enhancing the sustainability of worm control programs.
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Emodepside, a semi-synthetic derivative of PF1022A, belongs to a new class of anthelmintic drugs, the cyclooctadepsipeptides, and shows good efficacy against macrocyclic lactone-, levamisole- or benzimidazole-resistant nematode populations. Although putative receptors for emodepside have already been discovered, its mode of action is still not fully understood. The involvement of the γ-aminobutyric acid (GABA)-receptor on the PF1022A mode of action has previously been postulated. Therefore, a possible role of the GABA-receptor, unc-49, in the mode of action of emodepside was investigated using two different Caenorhabditis elegans in vitro assays, a motility assay and a development assay. It was found that there is a clearly reduced sensitivity against emodepside of strains carrying a GABA-receptor, unc-49, loss of function mutation compared with N2 wild type C. elegans. To transfer these results from the model system to parasitic nematodes, the Toxocara canis unc-49B cDNA sequence was identified and used in a rescue experiment. The emodepside-susceptible phenotype could be fully rescued by injection of the T. canis unc-49B cDNA sequence. We believe that this is the first functional rescue of a C. elegans mutant strain with a gene from a clade III parasitic nematode. These findings, together with the earlier data on GABA-receptor binding of PF1022A, suggest that the GABA(A)-receptor UNC-49 is associated with the emodepside mode of action. However, the only partially resistant phenotype of the loss of function mutants indicates that other pathways play a more significant role.
Article
Drug resistance in gastrointestinal nematodes is a severe problem for sheep farmers. With the recent introduction of monepantel (Zolvix®) and of derquantel plus abamectin (Startect®) in New Zealand, two new anthelmintic classes will be available to control gastrointestinal nematodes. While monepantel covers a broad spectrum of nematodes, the efficacy of derquantel is mid-spectrum and limited to a smaller number of species and stages. The combination of derquantel and abamectin allows to enlarge the spectrum and to cover most parasitic nematodes in sheep. However, the question remained open, if the efficacy of the new anthelmintics can be maintained in the presence of severe anthelmintic resistance. The present study investigated the efficacy against adult stages of a multi-resistant Haemonchus contortus isolate. While monepantel resulted in 100 % elimination, derquantel in combination with abamectin resulted in efficacies <95 % (faecal egg counts and worm counts).
Article
The objective of the present studies was to evaluate the efficacy of a combined formulation (Startect(®) Dual Active Oral Solution for Sheep, Pfizer Animal Health) of derquantel (DQL) and abamectin (ABA) for the treatment of: (1) sheep experimentally infected with a moxidectin (MOX)-resistant isolate of Teladorsagia circumcincta, and (2) multi-drug resistant gastrointestinal nematode parasites under UK field conditions. In the first study, a total of 40 animals were allocated into 4 treatment groups, and were either left untreated or treated with DQL+ABA, MOX or ABA. Faecal samples were collected on days 1-5 and on day 7 after treatment to examine the reduction in faecal egg excretion and to evaluate the egg viability. On day 14 post treatment all animals were euthanised for abomasal worm counts. There was a 100% reduction in geometric mean worm counts for the DQL+ABA treated animals compared to the untreated control animals (P<0.0001), whereas the percentage reduction in worm counts for the MOX- (P>0.05) and ABA-treated (P=0.0004) animals was 12.4% and 71.8%, respectively. The data from the egg hatch assay (EHA) indicated that in the MOX-treated and the ABA-treated animals, the majority of the eggs hatched after treatment. In the field study, performed on four farms, animals were allocated into 6 groups of 11-15 animals each in order to conduct a faecal egg count reduction test (FECRT), based on arithmetic mean egg counts. One group of animals remained untreated, whereas the other animals were treated with DQL+ABA, MOX, fenbendazole (FBZ), levamisole (LV) or ivermectin (IVM). On each of the farms the reduction in egg excretion after treatment with FBZ, LV or IVM was below 95.0%, indicating anthelmintic resistance. The efficacy of DQL+ABA ranged from 99.1 to 100%, yielding significantly lower egg counts compared to the untreated control group (P≤0.003). For MOX the egg counts were significantly (P≤0.003) lower compared to the untreated group at each farm, with reductions varying from 98.2 to 100%. The post-treatment copro-cultures for larva identification indicated that T. circumcincta was the most abundant worm species after treatment (52-99% of the larvae). The results of these studies confirm the high efficacy of the DQL+ABA combination formulation against anthelmintic resistant nematodes in the UK.
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The genotoxicity of a variety of aniline derivatives was examined by a DNA repair test with rat hepatocytes. Out of 37 aniline derivatives, 6 chemicals, i.e., 2,4,6-trimethylaniline (mesidine), 2,4-xylidine, 3,5-diaminobenzoic acid, 3,4-diaminochlorobenzene, 2-chloro-4-methylaniline and 4-chloro-N-methyl-aniline, elicited positive DNA repair responses. The results are in agreement with the bacterial mutagenicities with or without norharman of these compounds. Positive compounds of unknown carcinogenicity in the present assay, i.e., 3,5-diaminobenzoic acid, 2-chloro-4-methylaniline and 4-chloro-N-methylaniline are suspected of being potentially carcinogenic.
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The inhibition of Teladorsagia and other nematode genera at the early fourth-stage is a biological process that allows the parasites to survive in their host in a dormant state when prevailing conditions may otherwise kill them or prevent their progeny from surviving in the external environment. A study was conducted in Scotland to evaluate the efficacy of monepantel, an amino-acetonitrile derivative, against natural infections of inhibited fourth-stage Teladorsagia spp. larvae. At necropsy it was determined that the untreated control sheep were additionally infected with developing fourth-stage Teladorsagia spp. larvae and this is the first published evidence on the efficacy of monepantel against natural infections of this parasite and stage. The study sheep, which had grazed on naturally contaminated pastures since birth, were transferred to indoor housing after a subset of animals was examined to confirm the presence of inhibited larvae within the study population prior to the experiment. After 14 days of housing, monepantel was orally administered at 2.5 mg/kg to half of the animals. The sheep were necropsied seven days later and their parasite burdens recovered for the determination of efficacy, which was 99.7% for the inhibited stages and 99.3% for the developing fourth-stages. In conclusion, monepantel dosed orally at 2.5 mg/kg is a highly effective treatment against naturally acquired infections of inhibited and developing fourth-stage larvae of Teladorsagia spp.
Article
Three experiments defined the resistance profile of a population of Haemonchus contortus, which was shown to express multiple resistances to the benzimidazole, levamisole, macrocyclic lactone and salicylanilide anthelmintic classes when given as a registered combination. Study 1 was a faecal egg count reduction (FECR) test and the efficacies for the anthelmintics were monepantel, 100%; abamectin+levamisole+oxfendazole, 40.0%; and abamectin+levamisole+oxfendazole+naphthalophos, 100%. No larvae were recovered from the post-treatment cultures for monepantel or the 4-way treatment, and for the 3-way treatment the culture was 100% Haemonchus spp. Efficacies in Study 2 were calculated from mean post-mortem nematode burdens of H. contortus and were levamisole+oxfendazole, 3.1%; abamectin+levamisole+oxfendazole, 5.0%; ivermectin, 0.4%; moxidectin, 28.4% and closantel, 70.2%. Study 3 was also a FECR test that resulted in efficacies of 100% for monepantel and 83.0% for a formulated 4-way combination of abamectin+levamisole+albendazole+closantel. Larvae recovered from the post-treatment culture for the combination-treated sheep were all Haemonchus spp. Multi-resistant parasites such as examined in these studies are a continuing challenge to be managed by farmers and their advisors. Control programs must be planned and well-managed, and should include on-farm testing for anthelmintic resistance, monitoring of nematode burdens (by FEC and larval culture) to determine appropriate treatment times and the management of pastures to reduce the overall parasite challenge. This should be in balance with the generation, use and maintenance of drug-susceptible nematode populations in refugia.
Article
Over the past 10-15 years, we have witnessed a rapid increase in both the prevalence and magnitude of anthelmintic resistance, and this increase appears to be a worldwide phenomenon. Reports of anthelmintic resistance to multiple drugs in individual parasite species, and in multiple parasite species across virtually all livestock hosts, are increasingly common. In addition, since the introduction of ivermectin in 1981, no novel anthelmintic classes were developed and introduced for use in livestock until recently with the launch of monepantel in New Zealand. Thus, livestock producers are often left with few options for effective treatment against many important parasite species. While new anthelmintic classes with novel mechanisms of action could potentially solve this problem, new drugs are extremely expensive to develop, and can be expected to be more expensive than older drugs. Thus, it seems clear that the "Global Worming" approach that has taken hold over the past 40-50 years must change, and livestock producers must develop a new vision for parasite control and sustainability of production. Furthermore, parasitologists must improve methods for study design and data analysis that are used for diagnosing anthelmintic resistance, especially for the fecal egg count reduction test (FECRT). Currently, standards for diagnosis of anthelmintic resistance using FECRT exist only for sheep. Lack of standards in horses and cattle and arbitrarily defined cutoffs for defining resistance, combined with inadequate analysis of the data, mean that errors in assigning resistance status are common. Similarly, the lack of standards makes it difficult to compare data among different studies. This problem needs to be addressed, because as new drugs are introduced now and in the future, the lack of alternative treatments will make early and accurate diagnosis of anthelmintic resistance increasingly important.
Article
During the past two decades anthelmintic resistance in equine parasites has been found in the group of small strongyle species (cyathostomins) and in the ascarid species Parascaris equorum. The ubiquitous nature and possible severe consequences of disease with these nematodes make them the prime targets of current worm control programmes. Traditional control strategies mainly rely on the strategic application of anthelmintics, currently represented by three major drug classes: benzimidazoles (BZ), the tetrahydropyrimidine pyrantel (PYR) and macrocyclic lactones (ML). Following decades of routine and frequent anthelmintic applications, many cyathostomin populations on horse farms in industrialised countries must be considered as resistant to BZ anthelmintics. However, to date no published cases of cyathostomin disease specifically associated with anthelmintic resistance were reported. Possibly this is due to the generally subclinical and unspecific symptoms associated with cyathostomin infections. Nevertheless, exclusive reliance on the ML drug class may increase the threat of clinical disease due to drug-resistant cyathostomins.
Article
To observe the efficacy of oral administration of tribendimidine (TBD) at different dosages against Trichinella spiralis encapsulated larvae in murine striated muscle. A total of 88 BALB/c mice were divided equally into 11 groups. Each mouse was infected orally with 50 T spiralis encapsulated larvae. At day 29 after infection, TBD was each orally administered to mice of the 11 groups with doses of 0 (control group), 50, 100, 150, 200, 250, 300, 350, 400, 450, and 500 mg/(kg x d), respectively. All mice were administered once a day and lasted for 6d, and untoward drug reactions for mice were observed. Mice were sacrificed at the 7th day after administration of TBD, the encapsulated larvae in diaphragmatic muscle, jugomaxillary muscle, pectoral muscle and gastrocnemius muscle were examined by pellet method, and the total, survival and dead worms were counted. The therapeutic effect was estimated on the basis of average quantity of encapsulated larvae per gram muscle. During the administration period, no untoward reaction were observed in mice of 50-300 mg/(kg x d) groups. Mice in 350 and 400 mg/(kg x d) groups showed body hair dishevelment, emaciation and food-intake decrease, death rates were 25% and 50%, respectively. All mice in 450 and 500 mg/(kg x d) groups died on day 4 and 5 after TBD administration, respectively. In control group, the highest total burden (per gram) was found in diaphragmatic muscle, followed by jugomaxillary muscle, gastrocnemius muscles and pectoral muscles. TBD at dose of 50 mg/(kg x d) was unable to kill encapsulated larvae. In the rest groups, with the increase of drug dose, the total worm burden and the number of survival worms showed a decreasing trend in four kinds of muscles, and were significantly lower than that of the control group (P < 0.05 or P < 0.01). In 300 mg/(kg x d) group the number of survival worms in diaphragmatic muscle, jugomaxillary muscle, pectoral muscle and gastrocnemius muscle [8.6 +/- 1.7, 2.8 +/- 0.7, 3.9 +/- 0.8, and 0, respectively] were significantly lower than that of the control group [3648.1 +/- 989.2, 1266.4 +/- 812.3, 701.9 +/- 196.4, and 711.6 +/- 34.6] (P < 0.01). All encapsulated larvae in the four kinds of muscle died in 350 and 400 mg/(kg x d) groups. With the increase of TBD dosage, the mortality of encapsulated larvae increased in the muscles, reached up to 98.6%--100% in 300 m (kg x d) group (P < 0.01), and 100% in 350 and 400 mg/(kg x d) groups (P < .01). Oral tribendimidine administered at 50 mg/(kg x d) to mice for 6 d is unable to reduce worm burden in muscle. Tribendimidine 300 mg/(kg x d) effectively kill encapsulated larvae and is a suitable dose against encapsulated larva stage. However, tribendimidine at doses of 350 mg/(kg x d) and above for 6d is toxic to mice and even causing death.