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1.
Nature ; 452(7184): 176-80, 2008 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-18337814

RESUMEN

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/farmacología , Antihelmínticos/clasificación , Antihelmínticos/farmacología , Resistencia a Medicamentos , Nematodos/efectos de los fármacos , Enfermedades Parasitarias en Animales/parasitología , Envejecimiento , Secuencia de Aminoácidos , Aminoacetonitrilo/efectos adversos , Aminoacetonitrilo/farmacocinética , Animales , Antihelmínticos/química , Antihelmínticos/farmacocinética , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/parasitología , Resistencia a Medicamentos/genética , Larva/efectos de los fármacos , Larva/genética , Datos de Secuencia Molecular , Nematodos/genética , Nematodos/fisiología , Enfermedades Parasitarias en Animales/tratamiento farmacológico , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Ovinos/parasitología , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/parasitología
2.
FASEB J ; 26(11): 4650-61, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22889830

RESUMEN

The heartworm Dirofilaria immitis is an important parasite of dogs. Transmitted by mosquitoes in warmer climatic zones, it is spreading across southern Europe and the Americas at an alarming pace. There is no vaccine, and chemotherapy is prone to complications. To learn more about this parasite, we have sequenced the genomes of D. immitis and its endosymbiont Wolbachia. We predict 10,179 protein coding genes in the 84.2 Mb of the nuclear genome, and 823 genes in the 0.9-Mb Wolbachia genome. The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States. The differential presence of anabolic pathways such as heme and nucleotide biosynthesis hints at the intricate metabolic interrelationship between the heartworm and Wolbachia. Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates. This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.


Asunto(s)
Antihelmínticos/farmacología , Dirofilaria immitis/genética , Dirofilariasis/parasitología , Enfermedades de los Perros/parasitología , Genoma de los Helmintos , Vacunas/inmunología , Animales , Antihelmínticos/uso terapéutico , Dirofilaria immitis/efectos de los fármacos , Dirofilaria immitis/inmunología , Dirofilaria immitis/microbiología , Dirofilariasis/tratamiento farmacológico , Dirofilariasis/prevención & control , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/prevención & control , Perros , Femenino , Variación Genética , Genoma Bacteriano , Masculino , Filogenia , Proteoma , ARN de Helminto/química , Simbiosis , Transcriptoma/genética , Wolbachia/genética , Wolbachia/fisiología
3.
PLoS Pathog ; 6(9): e1001091, 2010 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-20838602

RESUMEN

The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL-1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC(50)<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC(50)>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/farmacología , Resistencia a Medicamentos/genética , Genoma de los Helmintos , Canales Iónicos Activados por Ligandos/genética , Filogenia , Aminoacetonitrilo/farmacología , Animales , Antinematodos/farmacología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Hemoncosis/tratamiento farmacológico , Hemoncosis/genética , Hemoncosis/parasitología , Haemonchus/efectos de los fármacos , Haemonchus/genética , Haemonchus/patogenicidad , Canales Iónicos Activados por Ligandos/metabolismo , Nematodos/efectos de los fármacos , Nematodos/genética , Nematodos/patogenicidad , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/genética , Infecciones por Nematodos/parasitología , Recuento de Huevos de Parásitos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/genética , Enfermedades de las Ovejas/parasitología , Resultado del Tratamiento
4.
Parasitol Res ; 111(5): 2205-7, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22576857

RESUMEN

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).


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/administración & dosificación , Hemoncosis/tratamiento farmacológico , Haemonchus/efectos de los fármacos , Indoles/administración & dosificación , Ivermectina/análogos & derivados , Oxepinas/administración & dosificación , Aminoacetonitrilo/administración & dosificación , Aminoacetonitrilo/farmacología , Animales , Antihelmínticos/farmacología , Modelos Animales de Enfermedad , Heces/parasitología , Indoles/farmacología , Ivermectina/administración & dosificación , Ivermectina/farmacología , Oxepinas/farmacología , Recuento de Huevos de Parásitos , Ovinos , Resultado del Tratamiento
5.
PLoS Pathog ; 5(4): e1000380, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19360096

RESUMEN

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.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/farmacología , Resistencia a Medicamentos/genética , Haemonchus/genética , Proteínas del Helminto/genética , Receptores Nicotínicos/genética , Secuencia de Aminoácidos , Aminoacetonitrilo/farmacología , Animales , Biblioteca de Genes , Genes de Helminto , Haemonchus/metabolismo , Datos de Secuencia Molecular , Mutación , Filogenia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
6.
Parasitol Res ; 109(1): 19-23, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21161271

RESUMEN

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%).


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/administración & dosificación , Resistencia a Medicamentos , Ivermectina/análogos & derivados , Infecciones por Nematodos/veterinaria , Enfermedades de las Ovejas/tratamiento farmacológico , Ovinos/parasitología , Aminoacetonitrilo/administración & dosificación , Animales , Australia , Haemonchus/efectos de los fármacos , Haemonchus/aislamiento & purificación , Ivermectina/administración & dosificación , Larva/efectos de los fármacos , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/parasitología , Enfermedades de las Ovejas/parasitología , Resultado del Tratamiento , Trichostrongylus/efectos de los fármacos , Trichostrongylus/aislamiento & purificación
7.
Artículo en Inglés | MEDLINE | ID: mdl-34030109

RESUMEN

Dirofilaria immitis, also known as heartworm, is a major parasitic threat for dogs and cats around the world. Because of its impact on the health and welfare of companion animals, heartworm disease is of huge veterinary and economic importance especially in North America, Europe, Asia and Australia. Within the animal health market many different heartworm preventive products are available, all of which contain active components of the same drug class, the macrocyclic lactones. In addition to compliance issues, such as under-dosing or irregular treatment intervals, the occurrence of drug-resistant heartworms within the populations in the Mississippi River areas adds to the failure of preventive treatments. The objective of this review is to provide an overview of the disease, summarize the current disease control measures and highlight potential new avenues and best practices for treatment and prevention.


Asunto(s)
Enfermedades de los Gatos , Dirofilaria immitis , Dirofilariasis , Enfermedades de los Perros , Animales , Gatos , Dirofilariasis/tratamiento farmacológico , Dirofilariasis/epidemiología , Dirofilariasis/prevención & control , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/prevención & control , Perros , Lactonas
8.
Vet Parasitol ; 290: 109369, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33548595

RESUMEN

These guidelines are intended to provide an in-depth review of current knowledge and assist the planning and implementation of studies for evaluating the efficacy of parasiticides in reducing transmission of vector-borne pathogens (VBPs) to dogs and cats. At present, the prevention of VBP transmission in companion animals is generally achieved through the administration of products that can repel or rapidly kill arthropods, thus preventing or interrupting feeding before transmission occurs. The present guidelines complement existing guidelines, which focus on efficacy assessment of parasiticides for the treatment, prevention and control of flea and tick infestations, but also give guidance for studies focused on other vectors (i.e. mosquitoes and phlebotomine sand flies). The efficacy of parasiticides in reducing VBP transmission can be evaluated through laboratory or field studies. As such, the present guidelines provide recommendations for these studies, representing a tool for researchers, pharmaceutical companies and authorities involved in the research, development and registration of products with claims for reducing VBP transmission in dogs and cats, respecting the overall principles of the 3Rs (replacement, reduction and refinement). Gaps in our current understanding of VBP transmission times are herein highlighted and the need for further basic research on related topics is briefly discussed.


Asunto(s)
Antiparasitarios/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades Parasitarias en Animales/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Medicina Veterinaria/normas , Animales , Enfermedades de los Gatos/parasitología , Gatos , Enfermedades de los Perros/parasitología , Perros , Sociedades Científicas/normas
9.
Mol Pharmacol ; 78(5): 895-902, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20679419

RESUMEN

Monepantel is the first drug of a new family of anthelmintics, the amino acetonitrile derivatives (AAD), presently used to treat ruminants infected with gastrointestinal nematodes such as Haemonchus contortus. Monepantel shows an excellent tolerability in mammals and is active against multidrug-resistant parasites, indicating that its molecular target is absent or inaccessible in the host and is different from those of the classic anthelmintics. Genetic approaches with mutant nematodes have suggested acetylcholine receptors of the DEG-3 subfamily as the targets of AADs, an enigmatic clade of ligand-gated ion channels that is specific to nematodes and does not occur in mammals. Here we demonstrate direct interaction of monepantel, its major active metabolite monepantel sulfone, and other AADs with potential targets of the DEG-3 subfamily of acetylcholine receptors. H. contortus DEG-3/DES-2 receptors were functionally expressed in Xenopus laevis oocytes and were found to be preferentially activated by choline, to permeate monovalent cations, and to a smaller extent, calcium ions. Although monepantel and monepantel sulfone did not activate the channels by themselves, they substantially enhanced the late currents after activation of the channels with choline, indicating that these AADs are type II positive allosteric modulators of H. contortus DEG-3/DES-2 channels. It is noteworthy that the R-enantiomer of monepantel, which is inactive as an anthelmintic, inhibited the late currents after stimulation of H. contortus DEG-3/DES-2 receptors with choline. In summary, we present the first direct evidence for interaction of AADs with DEG-3-type acetylcholine receptors and discuss these findings in the context of anthelmintic action of AADs.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/farmacología , Haemonchus/metabolismo , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Regulación Alostérica , Aminoacetonitrilo/química , Aminoacetonitrilo/farmacología , Animales , Antihelmínticos/química , Colina/farmacología , Femenino , Agonistas Nicotínicos/química , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Subunidades de Proteína/agonistas , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Receptores de GABA/metabolismo , Receptores Nicotínicos/genética , Estereoisomerismo , Sulfonas/química , Sulfonas/farmacología , Xenopus laevis
10.
Parasitol Res ; 106(2): 529-32, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19795134

RESUMEN

Monepantel is the first compound from the amino-acetonitrile derivative class of anthelmintics to be developed for the control of gastrointestinal nematodes of sheep. An analysis of pooled data from a series of controlled studies is reported providing a single point of efficacy (+/- 95% confidence interval) for each gastrointestinal nematode tested at the fourth larval and/or adult stages. For most nematode species, the pooled efficacy was greater than 99%, and for the remaining few species, efficacy was greater than 90%. These data are well supported by field studies conducted across five countries, where the pooled efficacy (on the basis of fecal worm egg count reduction) was in most cases, greater than 99% (depending on the calculation used). Monepantel is highly effective when administered to sheep at 2.5 mg/kg, and its introduction as a new anthelmintic for sheep is timely, given the problems with anthelmintic resistance that the world's sheep farmers are now experiencing.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/uso terapéutico , Enfermedades Gastrointestinales/veterinaria , Nematodos/aislamiento & purificación , Infecciones por Nematodos/veterinaria , Enfermedades de las Ovejas/tratamiento farmacológico , Aminoacetonitrilo/administración & dosificación , Aminoacetonitrilo/uso terapéutico , Animales , Antihelmínticos/administración & dosificación , Ensayos Clínicos Controlados como Asunto , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/parasitología , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/parasitología , Ovinos , Enfermedades de las Ovejas/parasitología , Resultado del Tratamiento
11.
Parasitol Res ; 106(2): 367-75, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19898870

RESUMEN

This analysis investigated the influence of breed and gender on the pharmacokinetics of monepantel, and influence of breed, age, and gender on its efficacy against gastrointestinal nematodes of sheep. In a comparison of pharmacokinetic profiles from two studies, Merino lambs had significantly greater maximum concentrations of monepantel and monepantel sulfone, and faster times to reach these concentrations than Dorset cross lambs. Males had a statistically greater area under the curve (0-504 h) than females for monepantel sulfone. The biological relevance of these relatively small differences is unclear because efficacy was not evaluated in these studies. For efficacy, a breed effect existed for some nematodes when sheep were treated at a sub-optimum dose (1.25 mg/kg). There were no gender effects between sheep infected with adult parasites and treated at 1.25 mg/kg but there were differences between females and males treated at this dose when infected with fourth-stage larvae of Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis, and Cooperia curticei. There were no breed or gender differences for sheep treated at the recommended dose (2.5 mg/kg). There was a potential trend for declining efficacy with increasing animal age for fourth-stage Trichostrongylus axei. This analysis demonstrated that, similarly to what is observed with other anthelmintics, the pharmacokinetics and efficacy of monepantel can vary with factors like breed, age, and gender. Identifying these covariates is important for understanding inter-individual variability in drug response. While further investigation is warranted, correctly treating sheep at the recommended dose of 2.5 mg/kg appears to mitigate any associated risk.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/farmacología , Antihelmínticos/farmacocinética , Helmintiasis Animal/tratamiento farmacológico , Enfermedades de las Ovejas/tratamiento farmacológico , Factores de Edad , Aminoacetonitrilo/farmacocinética , Aminoacetonitrilo/farmacología , Animales , Femenino , Masculino , Linaje , Factores Sexuales , Ovinos
12.
Vet Parasitol ; 159(1): 49-54, 2009 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-19019553

RESUMEN

Multiple drug resistance by nematodes, against anthelmintics has become an important economic problem in sheep farming worldwide. Here we describe the efficacy of monepantel, a developmental molecule from the recently discovered anthelmintic class, the amino-acetonitrile derivatives (AADs). Efficacy was tested against adult stage gastro-intestinal nematodes (GINs) in experimentally and naturally infected sheep at a dose of 2.5mg/kg body weight when administered as an oral solution. Some of the isolates used in experimental infection studies were known to be resistant to the benzimidazoles or levamisole anthelmintics; strains resistant to the macrocyclic lactones were not available for these tests. Worm count-based efficacies of >98% were determined in these studies. As an exception, Oesophagostomum venulosum was only reduced by 88% in one study, albeit with a low worm burden in the untreated controls (geometric mean 15.4 worms). Similar efficacies for monepantel were also confirmed in naturally infected sheep. While the efficacy against most species was >99%, the least susceptible species was identified as Nematodirus spathiger, and although efficacy was 92.4% in one study it was generally >99%. Several animals were infected with Trichuris ovis, which was not eliminated after the treatment. Monepantel demonstrated high activity against a broad range of the important GINs of sheep, which makes this molecule an interesting candidate for use in this species, particularly in regions with problems of anthelmintic resistance. Monepantel was well tolerated by the treated sheep, with no treatment related adverse events documented.


Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos/farmacología , Enfermedades Gastrointestinales/veterinaria , Nematodos/efectos de los fármacos , Infecciones por Nematodos/veterinaria , Enfermedades de las Ovejas/tratamiento farmacológico , Aminoacetonitrilo/administración & dosificación , Aminoacetonitrilo/farmacología , Aminoacetonitrilo/uso terapéutico , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/uso terapéutico , Enfermedades Gastrointestinales/tratamiento farmacológico , Nematodos/aislamiento & purificación , Infecciones por Nematodos/tratamiento farmacológico , Recuento de Huevos de Parásitos/veterinaria , Ovinos , Enfermedades de las Ovejas/parasitología
13.
Parasitol Res ; 105(3): 825-34, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19452165

RESUMEN

The ability to reliably detect anthelmintic resistance is a crucial part of resistance management. If data between countries are to be compared, the same test should give the same results in each laboratory. As the egg hatch test for benzimidazole resistance is used for both research and surveys, the ability of different laboratories to obtain similar results was studied through testing of known isolates of cyathostomins, Haemonchus contortus, Ostertagia ostertagi, and Cooperia oncophora in programs supported by the EU (Cost B16 and FP6-PARASOL). Initial results showed difficulties in obtaining reproducible and similar data within and between laboratories. A series of ring tests, i.e., simultaneous and coordinated rounds of testing of nematode isolates in different laboratories was subsequently performed. By adopting identical protocols, especially the use of deionized water and making dilutions of thiabendazole in dimethyl sulfoxide in the final ring test, laboratories correctly identified both susceptible and resistant isolates. The protocols for the test and preparation of solutions of thiabendazole are described.


Asunto(s)
Antihelmínticos/farmacología , Bencimidazoles/farmacología , Resistencia a Medicamentos , Nematodos/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria/métodos , Pruebas de Sensibilidad Parasitaria/normas , Animales , Huevos , Haemonchus/efectos de los fármacos , Ostertagia/efectos de los fármacos , Reproducibilidad de los Resultados , Trichostrongyloidea/efectos de los fármacos
14.
Bioorg Med Chem Lett ; 18(9): 2935-8, 2008 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-18400497

RESUMEN

A new series of amino-acetonitrile derivatives (AAD) have been discovered that exhibit high anthelmintic activity against parasitic nematode species such as Haemonchus contortus and Trichostrongylus colubriformis. Significantly, these compounds also demonstrate activity against nematode strains resistant to the currently available broad-spectrum anthelmintics. The discovery, synthesis, structure-activity relationship and biological results are presented.


Asunto(s)
Aminoacetonitrilo/farmacología , Antihelmínticos/farmacología , Haemonchus/efectos de los fármacos , Trichostrongylus/efectos de los fármacos , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/síntesis química , Animales , Antihelmínticos/síntesis química , Relación Dosis-Respuesta a Droga , Modelos Químicos , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad
15.
Trends Parasitol ; 34(2): 99-101, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29191558

RESUMEN

The need to improve parasite control to overcome drug-resistant parasite populations, and to improve compliance by more convenient drug application methods, is evident. While a number of incremental stepwise improvements are visible, the big disruptive innovation, an iPhone-equivalent breakthrough, has been hard to find. Why?


Asunto(s)
Resistencia a Medicamentos , Enfermedades Parasitarias/prevención & control , Animales , Antiparasitarios/normas , Antiparasitarios/uso terapéutico , Humanos , Enfermedades Parasitarias/tratamiento farmacológico , Investigación/normas , Investigación/tendencias
16.
Vet Parasitol ; 144(3-4): 313-20, 2007 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-17101226

RESUMEN

In order to monitor and eventually control the spread of drug-resistant Haemonchus contortus, knowledge of the molecular mechanisms underlying resistance is essential. Here we phenotypically and genotypically characterize three multidrug-resistant H. contortus field isolates from Australia and South Africa. All were significantly less susceptible to thiabendazole than a sensitive reference strain in an in vitro egg-hatch assay. The sensitivity was further reduced in a surviving population after treatment of infected sheep with albendazole. The beta-tubulin genes were amplified from genomic DNA of the H. contortus isolates, cloned, and sequenced. There was a high degree of sequence variation. The known mutation phenylalanine-200 to tyrosine (F200Y) occurred in 60% of the sequences from resistant isolates, but not in the sensitive reference. Interestingly, 90% of the beta-tubulin sequences from resistant isolates lacking tyrosine-200 carried another mutation nearby, glutamate-198 to alanine (E198A). This mutation was not found in the sensitive isolate, nor in sequences from resistant isolates carrying the mutation F200Y. However, the mutation E198A is known from benomyl-resistant isolates of phytopathogenic fungi such as Monilinia fructicola. The finding that alanine-198 correlates with thiabendazole resistance in H. contortus isolates from South Africa and Australia suggests that also in nematodes, the mutation E198A plays a role in benzimidazole resistance. Alanine-198 alleles of beta-tubulin can be detected by PCR-RFLP and we suggest to include this test in future surveys of H. contortus field populations.


Asunto(s)
Antihelmínticos/farmacología , Bencimidazoles/farmacología , Resistencia a Múltiples Medicamentos/genética , Haemonchus/efectos de los fármacos , Haemonchus/genética , Mutación/genética , Secuencia de Aminoácidos , Animales , Genotipo , Haemonchus/fisiología , Fenotipo , Polimorfismo Genético , Tubulina (Proteína)/química , Tubulina (Proteína)/genética
17.
Int J Parasitol Drugs Drug Resist ; 7(1): 90-109, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28189117

RESUMEN

Vector-borne diseases are responsible for significant health problems in humans, as well as in companion and farm animals. Killing the vectors with ectoparasitic drugs before they have the opportunity to pass on their pathogens could be the ideal way to prevent vector borne diseases. Blocking of transmission might work when transmission is delayed during blood meal, as often happens in ticks. The recently described systemic isoxazolines have been shown to successfully prevent disease transmission under conditions of delayed pathogen transfer. However, if the pathogen is transmitted immediately at bite as it is the case with most insects, blocking transmission becomes only possible if ectoparasiticides prevent the vector from landing on or, at least, from biting the host. Chemical entities exhibiting repellent activity in addition to fast killing, like pyrethroids, could prevent pathogen transmission even in cases of immediate transfer. Successful blocking depends on effective action in the context of the extremely diverse life-cycles of vectors and vector-borne pathogens of medical and veterinary importance which are summarized in this review. This complexity leads to important parameters to consider for ectoparasiticide research and when considering the ideal drug profile for preventing disease transmission.


Asunto(s)
Vectores Arácnidos , Infecciones/transmisión , Insectos Vectores , Enfermedades por Picaduras de Garrapatas/prevención & control , Enfermedades por Picaduras de Garrapatas/transmisión , Animales , Animales Domésticos/parasitología , Vectores Arácnidos/microbiología , Vectores Arácnidos/parasitología , Mordeduras y Picaduras , Descubrimiento de Drogas , Control de Infecciones , Insectos Vectores/microbiología , Insectos Vectores/parasitología , Piretrinas , Enfermedades por Picaduras de Garrapatas/parasitología
18.
Parasit Vectors ; 8: 119, 2015 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-25890350

RESUMEN

BACKGROUND: The lungworm Dictyocaulus viviparus, causing parasitic bronchitis in cattle, induces a temporary protective immunity that prevents clinical disease. A radiation-attenuated larvae based vaccine is commercially available in a few European countries, but has the disadvantages of a live vaccine. As a recombinant subunit vaccine would overcome these disadvantages, the parasite's muscle protein paramyosin (PMY) was tested as a recombinant vaccine antigen. METHODS: D. viviparus-PMY was recombinantly expressed in Escherichia coli as a glutathione-S-transferase (GST)-fused protein. Emulsified in adjuvant Saponin Quil A, the protein was given intramuscularly into calves. Two independent recombinant PMY (rPMY) vaccination trials with negative control groups (first trial: adjuvant only; second trial: non-fused GST) as well as an additional positive control group in the second trial, using the Bovilis Dictol live vaccine to verify vaccination results, were performed. To determine the vaccination success, shedding of larvae as well as worm burden and worm sizes were analyzed. Additionally, ELISA-based determination of development of immunglobulins IgM, IgA, IgE, IgG as well as the subclasses IgG1 and IgG2 was performed. To analyze PMY localization in the bovine lungworm, immunohistochemical staining of adult worms was carried out. RESULTS: Immunohistochemical staining revealed that PMY is part of the bovine lungworm's pharyngeal and body wall muscles. Vaccination with rPMY resulted in 47% [geometric mean: 67%] and 57% (geometric mean: 71%) reduction of larvae shedding in the first and second vaccination trial, respectively. Worm burden was reduced by 54% (geometric mean: 86%) and 31% (geometric mean: 68%), respectively, and worms of rPMY-vaccinated cattle were significantly shorter in both trials. Furthermore, ELISAs showed a clear antibody response towards rPMY with exception of IgE for which titers could not be detected. After challenge infection, rPMY antibodies were only exceptionally elevated among study animals indicating PMY to be a hidden antigen. CONCLUSIONS: Even though vaccination with the attenuated live vaccine was with 94% (geometric mean: 95%) reduction in larvae shedding and 93% (geometric mean: 94%) reduction in worm burden superior to rPMY vaccination, results using the latter are promising and show the potential for further development of a recombinant PMY-based vaccine against the bovine lungworm.


Asunto(s)
Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/inmunología , Enfermedades de los Bovinos/prevención & control , Infecciones por Dictyocaulus/prevención & control , Dictyocaulus/inmunología , Tropomiosina/inmunología , Vacunación/veterinaria , Animales , Bovinos , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/parasitología , Dictyocaulus/fisiología , Infecciones por Dictyocaulus/inmunología , Infecciones por Dictyocaulus/parasitología , Femenino , Larva , Masculino
19.
Vet Parasitol ; 210(3-4): 167-78, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-25936435

RESUMEN

Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom(®) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms.


Asunto(s)
Dirofilaria immitis/genética , Dirofilariasis/parasitología , Enfermedades de los Perros/parasitología , Filaricidas/farmacología , Lactonas/farmacología , Animales , Quimioprevención/veterinaria , Dirofilaria immitis/efectos de los fármacos , Perros , Resistencia a Medicamentos , Femenino , Marcadores Genéticos/genética , Ivermectina/farmacología , Macrólidos/farmacología , Masculino , Microfilarias , Polimorfismo de Nucleótido Simple/genética
20.
J Med Chem ; 45(14): 3067-72, 2002 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-12086492

RESUMEN

From a new tunicate species, belonging to the genus Didemnum, three alkaloids possessing an unusual and extremely rare decahydroquinoline skeleton and showing significant and selective antiplasmodial and antitrypanosomal activity were obtained as follows: (2R*,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methylquinoline (lepadin D,1), its quaternary nitrogen derivative (2), (2R*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin E, 3), and (2S*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin F, 4). These isolates may well serve as lead structures for the development of new antimalarial drugs.


Asunto(s)
Alcaloides/farmacología , Antiparasitarios/farmacología , Quinolinas/farmacología , Urocordados/química , Alcaloides/química , Alcaloides/aislamiento & purificación , Animales , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Antiparasitarios/química , Antiparasitarios/aislamiento & purificación , Australia , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Humanos , Espectroscopía de Resonancia Magnética , Plasmodium falciparum/efectos de los fármacos , Quinolinas/química , Quinolinas/aislamiento & purificación , Tripanocidas/química , Tripanocidas/aislamiento & purificación , Tripanocidas/farmacología , Trypanosoma brucei rhodesiense/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos
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