The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Achim Harder - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of Cyclooctadepsipeptides and Aminophenylamidines against Larval, Immature and Mature Adult Stages of a Parasitologically Characterized Trichurosis Model in Mice
2016Co-Authors: Daniel Kulke, Achim Harder, Georg Von Samson-himmelstjernaAbstract:Background: The genus Trichuris includes parasites of major relevance in veterinary and human medicine. Despite serious economic losses and enormous impact on public health, treatment options against whipworms are very limited. Additionally, there is an obvious lack of appropriately characterized experimental infection models. Therefore, a detailed parasitological characterization of a Trichuris muris isolate was performed in C57BL/10 mice. Subsequently, the in vivo efficacies of the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine as well as the cyclooctadepsipeptides Emodepside and in particular PF1022A were analyzed. This was performed using various administration routes and treatment schemes targeting histotropic and further developed larval as well as immature and mature adult stages. Methodology/Principal Findings: Duration of prepatent period, time-dependent localization of larvae during period of prepatency as well as the duration of patency of the infection were determined before drugs were tested in the characterized trichurosis model. Amidantel showed no effect against mature adult T. muris. Tribendimidine showed significantly higher potency than dAMD after oral treatments (ED50 values of 6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal treatments (ED50 values of 15.3 vs. 8.3 mg/kg). When Emodepside and PF1022A were compared, the latter was significantly less effective against mature adults following intraperitoneal (ED50 values of 6.1 vs. 55.7 mg/kg
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the cyclooctadepsipeptide anthelmintic Emodepside differentially modulates nematode insect and human calcium activated potassium slo channel alpha subunits
PLOS Neglected Tropical Diseases, 2015Co-Authors: Anna Crisford, Achim Harder, R J Walker, Vincent Oconnor, Eva Schoenhense, Klaus Raming, Kelechi Ndukwe, Ulrich Ebbinghauskintscher, Ita Okelly, Lindy HoldendyeAbstract:The anthelmintic Emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of Emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that Emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 μM intracellular Ca2+ and were strongly facilitated by Emodepside (100 nM; +73.0 ± 17.4%; n = 9; p<0.001). Drosophila Slo currents on the other hand were activated by Emodepside (10 μM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300nM Ca2+ and Emodepside transiently facilitated currents (100nM; +33.5 ± 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 ± 9.8%; n = 8; p<0.001). This first cross phyla comparison of the actions of Emodepside at nematode, insect and human channels provides new mechanistic insight into the compound’s complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of Emodepside as an anthelmintic treatment.
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Emodepside does not increase cytosolic Ca2+ in HEK293 cells.
2015Co-Authors: Anna Crisford, Achim Harder, Ulrich Ebbinghaus-kintscher, Eva Schoenhense, Klaus Raming, Ita O’kelly, Kelechi Ndukwe, Vincent O’connor, Robert J. Walker, Lindy Holden-dyeAbstract:Ca2+ fluorescence measured in HEK293 cells loaded with Fluo-3, AM dye after treatment with 1% DMSO (control), 100μM, 10μM, 1μM and 100nM Emodepside (1% DMSO) or ionomycin (1% DMSO). The Ca2+ fluorescence was measured at excitation of 480p and emission of 525p in the FLUO Star OPTIMA machine. The readings for each treatment were taken in triplicate. Data were pooled from at least three independent experiments and are shown as mean ± s.e.mean.
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Intracellular Ca2+ ions are required for Emodepside activation of Dm Slo.
2015Co-Authors: Anna Crisford, Achim Harder, Ulrich Ebbinghaus-kintscher, Eva Schoenhense, Klaus Raming, Ita O’kelly, Kelechi Ndukwe, Vincent O’connor, Robert J. Walker, Lindy Holden-dyeAbstract:A. Representative traces of Dm Slo whole cell currents stable expressed in CHO cells before (left hand traces) and after (right hand traces) Emodepside (10 μM) application at different free intracellular [Ca2+] (“0 nM”, 52 nM and 290 nM as indicated). Emodepside was applied for 10 min for experiments with low free intracellular [Ca2+] (“0 nM” and 52 nM). Membrane potential was held at -70 mV and stepped to between -120 and +60 mV in 10 mV increments for 100 ms. B. Current-voltage relationship of Dm Slo whole cell currents after Emodepside application at two different free intracellular Ca2+ concentrations, as indicated. Membrane potential was held at -70 mV and stepped to between -120 and +60 mV in 10 mV increments for 100 ms. Data points are the mean ± s.e.mean of n cell recordings.
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Emodepside increases Ce SLO-1 currents.
2015Co-Authors: Anna Crisford, Achim Harder, Ulrich Ebbinghaus-kintscher, Eva Schoenhense, Klaus Raming, Ita O’kelly, Kelechi Ndukwe, Vincent O’connor, Robert J. Walker, Lindy Holden-dyeAbstract:A. Representative traces of Ce SLO-1 whole cell currents expressed in HEK293 cells before (top trace) and (bottom trace) 12 min after Emodepside (100nM) application. Membrane potential was held at -60mV and stepped to between -100 and +90mV in 10mV increments for 50ms. B. A time-course of steady state Ce SLO-1 currents expressed in HEK293 cells at +70mV (stepped every 10s for 40ms from -60mV holding potential) before and during application of 0.01% DMSO or 100nM Emodepside. The current response is shown as a percentage change from the mean of pre-drug current amplitude during the 0 to 2 min time period. Arrow indicates the time of Emodepside application. Data points are the mean ± s.e.mean. Emodepside significantly increased the amplitude of the Ce SLO-1 currents, p
Gertraut Altreuther - One of the best experts on this subject based on the ideXlab platform.
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efficacy of Emodepside plus toltrazuril oral suspension for dogs procox bayer against trichuris vulpis in naturally infected dogs
Parasitology Research, 2013Co-Authors: Gabriele Petry, Gertraut Altreuther, Sonja Wolken, Petro Swart, Dawid J KokAbstract:The efficacy of Emodepside plus toltrazuril oral suspension for dogs (Procox®, Bayer) against Trichuris vulpis was evaluated in a controlled, blinded and randomised laboratory study. Twenty naturally infected dogs were included. Dogs in the treatment group received the minimum therapeutic dose of 0.45 mg Emodepside and 9 mg toltrazuril per kg body weight, while dogs in the control group were left untreated. Efficacy was calculated based on worm counts after necropsy on Day 7 post treatment. Additionally, all faeces were collected and examined for expelled worms. The treatment was 100 % effective. A total of 233 adult worms (geometric mean 17.0) and 3 immature adult worms were found in the control group at necropsy. Adequacy of infection was demonstrated. The treated group excreted a total of 186 adult worms within 2 days after treatment. Additionally, all dogs were co-infected with Uncinaria stenocephala. Efficacy against this parasite was 99.8 %. No side effects of the treatment were observed. This study demonstrates that in addition to the formerly proven efficacy against Toxocara canis, Ancylostoma caninum and Uncinaria stenocephala, Emodepside plus toltrazuril suspension is also effective against T. vulpis and thus represents a convenient treatment option for dogs co-infected with whipworms and coccidia.
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field evaluations of the efficacy and safety of Emodepside plus toltrazuril procox oral suspension for dogs against naturally acquired nematode and isospora spp infections in dogs
Parasitology Research, 2011Co-Authors: Gertraut Altreuther, Nadine Gasda, Kerstin Adler, Klaus Hellmann, Heloise Thurieau, Annette Schimmel, Douglas Hutchens, Klemens KriegerAbstract:Three controlled, blinded and randomised multicentre field studies evaluated the efficacy and safety of a new formulation containing Emodepside plus toltrazuril (Procox® suspension for dogs) against naturally acquired parasite infections in dogs. In two studies dogs positive for gastrointestinal nematodes and/or Isospora spp. were treated with Emodepside/toltrazuril suspension (at least 0.45 mg Emodepside plus 9 mg toltrazuril per kg body weight) or a reference product containing either milbemycin oxime plus praziquantel (Milbemax®) or sulfadimethoxine (Kokzidiol SD®) at recommended dose rates. The third study investigated efficacy against prepatent natural Isospora spp. infections in comparison to an untreated control group by enrolling Isospora- negative dogs that were at risk to develop a patent infection during the study.
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efficacy of Emodepside plus toltrazuril procox oral suspension for dogs against toxocara canis uncinaria stenocephala and ancylostoma caninum in dogs
Parasitology Research, 2011Co-Authors: Annette Schimmel, Gertraut Altreuther, Iris Schroeder, Terry Settje, Samuel Charles, Sonja Wolken, Dawid J Kok, Jennifer Ketzis, David Young, Douglas HutchensAbstract:The efficacy of Emodepside plus toltrazuril (Pro-and between 4 and 655 worms for hookworms. The cox® oral suspension for dogs) against different studies demonstrated 100 % efficacy of Emodepside/ species of gastrointestinal nematodes (Toxocara toltrazuril suspension against mature adult, ≥94.7% canis, Ancylostoma caninum, Uncinaria steno-efficacy against immature adult and 99.3 % efficacy cephala) was evaluated in nine randomised, against the L4 larval stage of T. canis. The efficacy blinded and placebo-controlled laboratory studies against mature adult A. caninum was ≥ 99.5 % and in naturally or experimentally infected dogs. The the efficacy against mature adult U. stenocephala product was used at the proposed minimum dose was 100 %. All differences between treatment and of 0.45 mg Emodepside and 9 mg toltrazuril per control groups were statistically significant and no kg body weight. Efficacy was calculated based on gender effect was found. It can be concluded that the worm counts after necropsy.
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efficacy of Emodepside plus toltrazuril suspension procox oral suspension for dogs against prepatent and patent infection with isospora canis and isospora ohioensis complex in dogs
Parasitology Research, 2011Co-Authors: Gertraut Altreuther, Nadine Gasda, Annette Schimmel, Douglas Hutchens, Iris Schroeder, Terry Settje, Anja Joachim, Klemens KriegerAbstract:Three randomised, blinded and placebo-controlled laboratory studies were conducted to evaluate the efficacy of Emodepside plus toltrazuril suspension (Procox® suspension for dogs) against Isospora canis and Isospora ohioensis-complex. Unweaned puppies were experimentally infected with sporulated oocysts of I. canis and/or I. ohioensis-complex. In each study, one group was treated during prepatency (2 or 4 days post infection) while dogs in the second group were treated individually after the onset of oocyst excretion of the respective coccidia species. The dogs were treated with the minimum therapeutic dose of 0.45 mg Emodepside and 9 mg toltrazuril per kg body weight. Daily faecal oocyst counts from both groups were compared to placebotreated control groups to determine efficacy.
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Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Adult Ancylostoma caninum and Uncinaria stenocephala Infections in Dogs
Parasitology Research, 2009Co-Authors: Annette Schimmel, Gertraut Altreuther, Iris Schroeder, Samuel Charles, Dawid J Kok, Jennifer Ketzis, L. Cruthers, Friederike Kraemer, John W. Mccall, K. J. KriegerAbstract:This paper reports the efficacy of a novel flavoured tablet formulation of Emodepside plus praziquantel (Profender® tablets for dogs) against mature and immature adult hookworms ( Ancylostoma caninum and Uncinaria stenocephala ) in dogs. The tablets were used at the minimum recommended dose of 1 mg Emodepside and 5 mg praziquantel per kg body weight. Four randomised, blinded and controlled laboratory studies demonstrated >95% efficacy against mature and immature adult stages of U. stenocephala and four randomised, blinded and controlled laboratory studies demonstrated >98% efficacy against mature and immature adult stages of A. caninum . No side effects of the treatment were observed. It is concluded that the Emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature hookworms.
R J Walker - One of the best experts on this subject based on the ideXlab platform.
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the cyclooctadepsipeptide anthelmintic Emodepside differentially modulates nematode insect and human calcium activated potassium slo channel alpha subunits
PLOS Neglected Tropical Diseases, 2015Co-Authors: Anna Crisford, Achim Harder, R J Walker, Vincent Oconnor, Eva Schoenhense, Klaus Raming, Kelechi Ndukwe, Ulrich Ebbinghauskintscher, Ita Okelly, Lindy HoldendyeAbstract:The anthelmintic Emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of Emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that Emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 μM intracellular Ca2+ and were strongly facilitated by Emodepside (100 nM; +73.0 ± 17.4%; n = 9; p<0.001). Drosophila Slo currents on the other hand were activated by Emodepside (10 μM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300nM Ca2+ and Emodepside transiently facilitated currents (100nM; +33.5 ± 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 ± 9.8%; n = 8; p<0.001). This first cross phyla comparison of the actions of Emodepside at nematode, insect and human channels provides new mechanistic insight into the compound’s complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of Emodepside as an anthelmintic treatment.
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selective toxicity of the anthelmintic Emodepside revealed by heterologous expression of human kcnma1 in caenorhabditis elegans
Molecular Pharmacology, 2011Co-Authors: Anna Crisford, Achim Harder, R J Walker, Vincent Oconnor, Georg Von Samsonhimmelstjerna, Claudia Welz, Nina Krüger, Caitriona Murray, Richard Edwards, Lindy HoldendyeAbstract:Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of Emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10- to 100-fold less sensitive to Emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that Emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to Emodepside, consistent with a direct interaction of Emodepside with the channel. Taken together, these data predict an Emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infections.
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the calcium activated potassium channel slo 1 is required for the action of the novel cyclo octadepsipeptide anthelmintic Emodepside in caenorhabditis elegans
International Journal for Parasitology, 2007Co-Authors: Marcus Guest, Achim Harder, Kathryn Bull, R J Walker, Kiran Amliwala, Vincent Oconnor, Lindy Holdendye, Neil A HopperAbstract:The cyclo-octadepsipeptide anthelmintic, Emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug’s actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of Emodepside on the pharynx it remains sensitive to the inhibitory effects of Emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of Emodepside on locomotion. Therefore, Emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca2+-activated K+ channel. These mutants were highly resistant to the inhibitory effect of Emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that Emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of Emodepside, but are not themselves Emodepside hypersensitive, favours a model whereby Emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that Emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, Emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of Emodepside and suggest that Emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion.
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effects of the novel anthelmintic Emodepside on the locomotion egg laying behaviour and development of caenorhabditis elegans
International Journal for Parasitology, 2007Co-Authors: Kathryn Bull, Achim Harder, Lindy Holdendye, Neil A Hopper, Alan Cook, R J WalkerAbstract:Abstract Emodepside, a cyclooctadepsipeptide, is a broad-spectrum anthelmintic previously shown to paralyse body wall muscle and pharyngeal muscle in the model nematode Caenorhabditis elegans. We demonstrate that wild-type C. elegans L4 are less sensitive than adults to Emodepside in two independent assays of locomotor behaviour: body bend generation on agar (adult IC50 3.7 nM, L4 IC50 13.4 nM) and thrashing behaviour in liquid (thrashing behaviour as a % of controls after 1 h in 10 μM Emodepside: adults 16%, L4 worms 48%). We also show that continuous exposure of wild-type C. elegans to Emodepside throughout the life-cycle from egg onwards, slows worm development, an effect that is Emodepside concentration-dependent. The rate of worm-hatching from eggs on agar plates containing Emodepside was not significantly different from controls, suggesting that it is development post-hatching rather than hatching itself that is affected by the drug. Emodepside also inhibits wild-type C. elegans egg-laying, with acute exposure to the drug at 500 nM resulting in an almost total inhibition within the first hour. However, the rate of egg production was not inhibited and therefore Emodepside-treated worms became bloated with eggs, eventually rupturing. This suggests that the effect of Emodepside on reproduction is not due to an inhibition of egg production but rather a paralytic effect on the egg-laying muscles. These results, when coupled with previous research, suggest that Emodepside interferes with signalling at the neuromuscular junction on the body-wall muscles ( Willson et al., 2003 ), pharynx ( Willson et al., 2004 ) and egg-laying muscles and thus inhibits three important physiological functions: locomotion, feeding and reproduction.
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Emodepside a cyclo octadepsipeptide anthelmintic with a novel mode of action
Drugs of The Future, 2004Co-Authors: Kiran Amliwala, Achim Harder, Kathryn Bull, Lindy Holdendye, J Willson, R J WalkerAbstract:Due to the development of drug resistance, there is a continual need for new anthelmintics with novel modes of action. Emodepside, a cyclo-octadepsipeptide, was originally thought to modify GABAergic transmission in parasitic nematodes. However, more recent studies using the parasitic nematode Ascaris suum and the free-living nematode Caenorhabditis elegans indicate that Emodepside interacts with a presynaptic latrophilin receptor to release a transmitter or modulator. This presynaptic signaling pathway involves activation of a Gaq protein and phospholipase-?, which mobilizes diacylglycerol (DAG). DAG activates UNC-13, which in turn activates synaptobrevin to increase release of the transmitter or modulator. The released transmitter or modulator acts postsynaptically to modify pharyngeal and somatic body wall muscle activity.
K. J. Krieger - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Adult Trichuris vulpis Infections in Dogs
Parasitology Research, 2009Co-Authors: Annette Schimmel, Iris Schroeder, Samuel Charles, Dawid J Kok, L. Cruthers, Friederike Kraemer, K. J. KriegerAbstract:This paper reports on the efficacy of a novel flavoured tablet formulation of Emodepside plus praziquantel (Profender® tablets for dogs) against mature and immature adult whipworms ( Trichuris vulpis ) at the proposed minimum dose of 1 mg Emodepside and 5 mg praziquantel per kg body weight in dogs. Three randomised, blinded and controlled laboratory studies with naturally or experimentally infected dogs were performed. The first study was conducted as a dose determination study in experimentally infected dogs using three different dose levels, i.e., 0.5x, 1x and 2x the minimum therapeutic dose. Two further studies confirmed the efficacy of Emodepside plus praziquantel tablets against mature and immature adult T. vulpis at the recommended minimum dose. In all three studies, the efficacy against mature and immature adult T. vulpis was >99%. No side effects of the treatment were observed. It is concluded that the Emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature adult stages of T. vulpis in dogs.
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Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Adult Ancylostoma caninum and Uncinaria stenocephala Infections in Dogs
Parasitology Research, 2009Co-Authors: Annette Schimmel, Gertraut Altreuther, Iris Schroeder, Samuel Charles, Dawid J Kok, Jennifer Ketzis, L. Cruthers, Friederike Kraemer, John W. Mccall, K. J. KriegerAbstract:This paper reports the efficacy of a novel flavoured tablet formulation of Emodepside plus praziquantel (Profender® tablets for dogs) against mature and immature adult hookworms ( Ancylostoma caninum and Uncinaria stenocephala ) in dogs. The tablets were used at the minimum recommended dose of 1 mg Emodepside and 5 mg praziquantel per kg body weight. Four randomised, blinded and controlled laboratory studies demonstrated >95% efficacy against mature and immature adult stages of U. stenocephala and four randomised, blinded and controlled laboratory studies demonstrated >98% efficacy against mature and immature adult stages of A. caninum . No side effects of the treatment were observed. It is concluded that the Emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature hookworms.
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Field Evaluation of the Efficacy and Safety of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Naturally Acquired Nematode and Cestode Infections in Dogs
Parasitology Research, 2009Co-Authors: Gertraut Altreuther, Annette Schimmel, Isabelle Radeloff, Christophe Lesueur, K. J. KriegerAbstract:A controlled, blinded and randomised multicentre field study evaluated the efficacy and safety of a new anthelmintic tablet formulation containing Emodepside plus praziquantel (Profender® tablets for dogs) in the treatment of gastrointestinal nematode and cestode infections in dogs in France, Germany, Portugal and Slovakia. Dogs positive for nematodes and/or cestodes (demonstrated by faecal egg counts and/or the presence of proglottids) were treated with Emodepside plus praziquantel tablets (n = 239) or the reference product containing milbemycin oxime and praziquantel (Milbemax® [n = 115]) at the recommended dose rate. Two faecal samples collected between 7 and 13 days after treatment were evaluated for proglottids, nematode and cestode eggs. No suspected adverse drug reactions were observed in the study. The following parasite species were identified: Trichuris vulpis , Toxocara canis , Toxascaris leonina , Uncinaria stenocephala , Ancylostoma caninum , Dipylidium caninum , Taeniidae and Mesocestoides spp. Geometric mean nematode egg counts in dogs treated with Emodepside plus prazi quantel tablets were reduced by 99.9 % compared with a reduction of 99.6 % for the reference product. Statistical analysis demonstrated noninferiority of investigational versus reference product (p = 0.0342). None of the dogs treated with Emodepside plus praziquantel or reference product remained positive for cestodes after treatment. The study demonstrated that Emodepside plus praziquantel tablets are safe and highly efficacious against a broad spectrum of nematodes and cestodes under field conditions.
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Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Cestode Infections in Dogs
Parasitology Research, 2009Co-Authors: Iris Schroeder, Gertraut Altreuther, Annette Schimmel, Dawid J Kok, Manuela Schnyder, Peter Deplazes, K. J. KriegerAbstract:The efficacy of a novel flavoured tablet formulation of Emodepside plus praziquantel (Profender® tablets for dogs) against intestinal cestodes was investigated in four randomised, blinded placebocontrolled dose confirmation studies in dogs experimentally infected with Echinococcus granulosus or E. multilocularis and in dogs naturally infected with Dipylidium caninum or Taenia spp. The tablets were used at the minimum recommended dose of 1 mg Emodepside and 5 mg praziquantel per kg body weight. The studies demonstrated 100% efficacy against mature and immature E. granulosus and E. multilocularis and mature Taenia spp. and D. caninum . Additionally, one of the studies demonstrated non-interference of Emodepside with the efficacy of praziquantel against D. caninum . No side effects of the treatment were observed. It is concluded that Emodepside plus praziquantel tablets are safe and effective against mature and immature stages of E. granulosus and E. multilocularis and mature stages of Taenia spp. and D. caninum .
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Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Infections with Toxocara canis and Toxascaris leonina in Dogs
Parasitology Research, 2009Co-Authors: Gertraut Altreuther, Annette Schimmel, Iris Schroeder, Samuel Charles, Sonja Wolken, Dawid J Kok, David Young, Friederike Kraemer, Thomas Bach, K. J. KriegerAbstract:The efficacy of Emodepside plus praziquantel tablets (Profender® tablets for dogs) against mature adult, immature adult and larval stages of Toxocara canis and Toxascaris leonina was evaluated in ten randomised, blinded and placebo-controlled dose confirmation studies in naturally or experimentally infected dogs. The tablets were used at the proposed minimum dose of 1 mg Emodepside and 5 mg praziquantel per kg body weight. Efficacy was calculated based on worm counts after necropsy. Five studies demonstrated >99% efficacy against mature adult, >92% efficacy against immature adult, >98% efficacy against L4 and >94% efficacy against L3 larval stages of T. canis . Another five studies demonstrated >99% efficacy against mature and immature adult and >95% efficacy against L4 larval stages of T. leonina . No side effects of the treatment were observed. Emodepside plus praziquantel tablets thus provide a comprehensive new treatment option for ascarid infections in the dog.
Lindy Holdendye - One of the best experts on this subject based on the ideXlab platform.
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development of Emodepside as a possible adulticidal treatment for human onchocerciasis the fruit of a successful industrial academic collaboration
PLOS Pathogens, 2021Co-Authors: Jürgen Krücken, Lindy Holdendye, Jennifer Keiser, Simon Townson, Roger K Prichard, Benjamin L Makepeace, Marc P Hubner, Steffen Hahnel, Ivan ScandaleAbstract:Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of Emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, Emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop Emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer-DNDi partnership is an outstanding example of "One World Health," in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.
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the cyclooctadepsipeptide anthelmintic Emodepside differentially modulates nematode insect and human calcium activated potassium slo channel alpha subunits
PLOS Neglected Tropical Diseases, 2015Co-Authors: Anna Crisford, Achim Harder, R J Walker, Vincent Oconnor, Eva Schoenhense, Klaus Raming, Kelechi Ndukwe, Ulrich Ebbinghauskintscher, Ita Okelly, Lindy HoldendyeAbstract:The anthelmintic Emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of Emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that Emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 μM intracellular Ca2+ and were strongly facilitated by Emodepside (100 nM; +73.0 ± 17.4%; n = 9; p<0.001). Drosophila Slo currents on the other hand were activated by Emodepside (10 μM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300nM Ca2+ and Emodepside transiently facilitated currents (100nM; +33.5 ± 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 ± 9.8%; n = 8; p<0.001). This first cross phyla comparison of the actions of Emodepside at nematode, insect and human channels provides new mechanistic insight into the compound’s complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of Emodepside as an anthelmintic treatment.
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selective toxicity of the anthelmintic Emodepside revealed by heterologous expression of human kcnma1 in caenorhabditis elegans
Molecular Pharmacology, 2011Co-Authors: Anna Crisford, Achim Harder, R J Walker, Vincent Oconnor, Georg Von Samsonhimmelstjerna, Claudia Welz, Nina Krüger, Caitriona Murray, Richard Edwards, Lindy HoldendyeAbstract:Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of Emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10- to 100-fold less sensitive to Emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that Emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to Emodepside, consistent with a direct interaction of Emodepside with the channel. Taken together, these data predict an Emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infections.
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the calcium activated potassium channel slo 1 is required for the action of the novel cyclo octadepsipeptide anthelmintic Emodepside in caenorhabditis elegans
International Journal for Parasitology, 2007Co-Authors: Marcus Guest, Achim Harder, Kathryn Bull, R J Walker, Kiran Amliwala, Vincent Oconnor, Lindy Holdendye, Neil A HopperAbstract:The cyclo-octadepsipeptide anthelmintic, Emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug’s actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of Emodepside on the pharynx it remains sensitive to the inhibitory effects of Emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of Emodepside on locomotion. Therefore, Emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca2+-activated K+ channel. These mutants were highly resistant to the inhibitory effect of Emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that Emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of Emodepside, but are not themselves Emodepside hypersensitive, favours a model whereby Emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that Emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, Emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of Emodepside and suggest that Emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion.
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effects of the novel anthelmintic Emodepside on the locomotion egg laying behaviour and development of caenorhabditis elegans
International Journal for Parasitology, 2007Co-Authors: Kathryn Bull, Achim Harder, Lindy Holdendye, Neil A Hopper, Alan Cook, R J WalkerAbstract:Abstract Emodepside, a cyclooctadepsipeptide, is a broad-spectrum anthelmintic previously shown to paralyse body wall muscle and pharyngeal muscle in the model nematode Caenorhabditis elegans. We demonstrate that wild-type C. elegans L4 are less sensitive than adults to Emodepside in two independent assays of locomotor behaviour: body bend generation on agar (adult IC50 3.7 nM, L4 IC50 13.4 nM) and thrashing behaviour in liquid (thrashing behaviour as a % of controls after 1 h in 10 μM Emodepside: adults 16%, L4 worms 48%). We also show that continuous exposure of wild-type C. elegans to Emodepside throughout the life-cycle from egg onwards, slows worm development, an effect that is Emodepside concentration-dependent. The rate of worm-hatching from eggs on agar plates containing Emodepside was not significantly different from controls, suggesting that it is development post-hatching rather than hatching itself that is affected by the drug. Emodepside also inhibits wild-type C. elegans egg-laying, with acute exposure to the drug at 500 nM resulting in an almost total inhibition within the first hour. However, the rate of egg production was not inhibited and therefore Emodepside-treated worms became bloated with eggs, eventually rupturing. This suggests that the effect of Emodepside on reproduction is not due to an inhibition of egg production but rather a paralytic effect on the egg-laying muscles. These results, when coupled with previous research, suggest that Emodepside interferes with signalling at the neuromuscular junction on the body-wall muscles ( Willson et al., 2003 ), pharynx ( Willson et al., 2004 ) and egg-laying muscles and thus inhibits three important physiological functions: locomotion, feeding and reproduction.