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International Journal For Parasitology.... Dec 2018The third scientific meeting in the series "Anthelmintics: From Discovery to Resistance" was held in Indian Rocks Beach, Florida, at the end of January 2018. The meeting...
The third scientific meeting in the series "Anthelmintics: From Discovery to Resistance" was held in Indian Rocks Beach, Florida, at the end of January 2018. The meeting focused on a variety of topics related to the title, including the identification of novel targets and new leads, the mechanism of action of existing drugs and the genetic basis of resistance against them. Throughout there was an emphasis on the exploitation of new technologies and methods to further these aims. The presentations, oral and poster, covered basic, veterinary and medical science with strong participation by both academic and commercial researchers. This special issue contains selected papers from the meeting.
Topics: Animals; Anthelmintics; Congresses as Topic; Drug Delivery Systems; Drug Discovery; Humans; Ion Channels
PubMed: 30429103
DOI: 10.1016/j.ijpddr.2018.11.002 -
Molecules (Basel, Switzerland) Nov 2017The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of... (Review)
Review
The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards.
Topics: Animals; Anthelmintics; Antifungal Agents; Antiprotozoal Agents; Antiviral Agents; Artemisinins; Dioxanes; Dioxolanes; Heterocyclic Compounds; Peroxides
PubMed: 29099089
DOI: 10.3390/molecules22111881 -
International Journal of Molecular... Jul 2020Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their... (Review)
Review
Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics-a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine-have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.
Topics: Anthelmintics; Antineoplastic Agents; Benzimidazoles; Clinical Trials as Topic; Digestive System Neoplasms; Drug Discovery; Drug Repositioning; Drug Screening Assays, Antitumor; Humans; Salicylanilides; Signal Transduction
PubMed: 32668817
DOI: 10.3390/ijms21144957 -
Revista Brasileira de Parasitologia... 2019The purpose of this work was to identify, critically assess, and summarize available data from primary research about the anthelmintic resistance of injectable... (Meta-Analysis)
Meta-Analysis Review
The purpose of this work was to identify, critically assess, and summarize available data from primary research about the anthelmintic resistance of injectable macrocyclic lactones in cattle. Meta-analysis was performed to estimate the pooled Odds Ratio and 95% Confidence Intervals. Of the 1504 abstracts screened for eligibility, 80 were deemed relevant for full publication review. Thirteen publications were included in the qualitative synthesis and assessed for systematic bias. Only five studies were included in the quantitative analysis because they showed a low risk of producing biased results in all the parameters. The forest plot indicated four studies that discuss anthelmintic resistance (P<0.05), while only one study did not discuss anthelmintic resistance (P<0.05). The pooled estimate showed 0.59 (95% Confidence intervals: 0.08, 0.47) times higher odds for studies that report anthelmintic resistance than for studies reporting efficacious anthelmintic treatment, with significant and substantially low heterogeneity (I2=25%). Anthelmintic resistance to injectable macrocyclic lactones is a reality. There are need to improve methodological reporting in studies, which is a problem for investigations that involves systematic review and meta-analysis (SR-MA).
Topics: Animals; Anthelmintics; Cattle; Cattle Diseases; Drug Resistance; Gastrointestinal Diseases; Lactams, Macrocyclic; Nematode Infections
PubMed: 30892462
DOI: 10.1590/S1984-296120180093 -
Parasites & Vectors Nov 2022Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in...
Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility.
BACKGROUND
Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential.
METHODS
In vitro assays were used to investigate heather's anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition.
RESULTS
Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage.
CONCLUSIONS
Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe.
Topics: Animals; Sheep; Trichostrongylus; Larva; Polyphenols; Anthelmintics; Ericaceae; Nematoda; Ostertagia; Feces; Plant Extracts; Sheep Diseases
PubMed: 36333822
DOI: 10.1186/s13071-022-05531-0 -
Molecular Systems Biology May 2021Novel invertebrate-killing compounds are required in agriculture and medicine to overcome resistance to existing treatments. Because insecticides and anthelmintics are...
Novel invertebrate-killing compounds are required in agriculture and medicine to overcome resistance to existing treatments. Because insecticides and anthelmintics are discovered in phenotypic screens, a crucial step in the discovery process is determining the mode of action of hits. Visible whole-organism symptoms are combined with molecular and physiological data to determine mode of action. However, manual symptomology is laborious and requires symptoms that are strong enough to see by eye. Here, we use high-throughput imaging and quantitative phenotyping to measure Caenorhabditis elegans behavioral responses to compounds and train a classifier that predicts mode of action with an accuracy of 88% for a set of ten common modes of action. We also classify compounds within each mode of action to discover substructure that is not captured in broad mode-of-action labels. High-throughput imaging and automated phenotyping could therefore accelerate mode-of-action discovery in invertebrate-targeting compound development and help to refine mode-of-action categories.
Topics: Animals; Anthelmintics; Automation; Behavior, Animal; Caenorhabditis elegans; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Insecticides; Molecular Structure; Phenotype; Systems Biology
PubMed: 34031985
DOI: 10.15252/msb.202110267 -
Infectious Disorders Drug Targets 2019Today schistosomiasis, caused mainly by the three major schistosome species (S. mansoni, S. haematobium and S. japonicum), has for many decades and still continues to be... (Review)
Review
Today schistosomiasis, caused mainly by the three major schistosome species (S. mansoni, S. haematobium and S. japonicum), has for many decades and still continues to be on a rapid and swift rise globally, claiming thousands of lives every year and leaving 800 million people at the risk of infection. Due to the high prevalence of this disease and the steady increase in the infection rates, praziquantel (PZQ) remains the only effective drug against this acute disease although it has no effect on the juvenile schistosome parasite. However, no significant approaches have been made in recent years in the discovery of new or alternative drugs and unfortunately, resistance to this drug has been reported in some parts of the world. Therefore, it is imperative to develop a new drug for this debilitating disease. In this review, a brief history of past, present, and new promising anti-schistosomal drugs is presented.
Topics: Animals; Anthelmintics; Global Health; History, 20th Century; History, 21st Century; Humans; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 30599112
DOI: 10.2174/1871526519666181231153139 -
Blood Cancer Journal Jun 2020Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains...
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Topics: Animals; Anthelmintics; Antineoplastic Agents; Apoptosis; Drug Repositioning; Drug Resistance, Neoplasm; Humans; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 32591499
DOI: 10.1038/s41408-020-0339-9 -
International Journal For Parasitology.... Dec 2020Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense...
Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense against these infections. Unfortunately, resistance to these drugs is rampant and continues to spread. To improve treatment strategies, we must understand the genetics and molecular mechanisms that underlie resistance. Studies of the fungus Aspergillus nidulans and the free-living nematode Caenorhabditis elegans discovered that a beta-tubulin gene is mutated in benzimidazole (BZ) resistant strains. In parasitic nematode populations, three beta-tubulin alleles, F167Y, E198A, and F200Y, have long been correlated with resistance. Additionally, improvements in sequencing technologies have identified new alleles - E198V, E198L, E198K, E198I, and E198Stop - also correlated with BZ resistance. However, none of these alleles have been proven to cause resistance. To empirically demonstrate this point, we independently introduced the F167Y, E198A, and F200Y alleles as well as two of the newly identified alleles, E198V and E198L, into the BZ susceptible C. elegans N2 genetic background using the CRISPR-Cas9 system. These genome-edited strains were exposed to both albendazole and fenbendazole to quantitatively measure animal responses to BZs. We used a range of concentrations for each BZ compound to define response curves and found that all five of the alleles conferred resistance to BZ compounds equal to a loss of the entire beta-tubulin gene. These results prove that the parasite beta-tubulin alleles cause resistance. The E198V allele is found at low frequencies along with the E198L allele in natural parasite populations, suggesting that it could affect fitness. We performed competitive fitness assays and demonstrated that the E198V allele reduces animal health, supporting the hypothesis that this allele might be less fit in field populations. Overall, we present a powerful platform to quantitatively assess anthelmintic resistance and effects of specific resistance alleles on organismal fitness in the presence or absence of the drug.
Topics: Alleles; Animals; Anthelmintics; Benzimidazoles; Caenorhabditis elegans; Drug Resistance; Humans; Tubulin
PubMed: 32858477
DOI: 10.1016/j.ijpddr.2020.08.003 -
International Journal For Parasitology.... Apr 2022Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In... (Review)
Review
Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.
Topics: Acetylcholine; Animals; Anthelmintics; Nematoda; Receptors, GABA; Receptors, Nicotinic
PubMed: 35149380
DOI: 10.1016/j.ijpddr.2021.12.001