Characterization of Moxidectin against <i>Strongyloides ratti</i>: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

Buchter, Valentin; Hofmann, Daniela; Häberli, Cécile; Keiser, Jennifer

doi:10.1021/acsinfecdis.0c00435

Cited by 9 publications

(17 citation statements)

References 31 publications

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“…Our in-depth study on a wide range of derivatives of benzimidazoles showed that these drugs would not offer a benefit over the two recommended human drugs, albendazole and mebendazole. Our study confirms that moxidectin is a useful addition to the human drug armamentarium as highlighted in previous laboratory and human studies. ,, There is an urgent need to discover novel drug classes as emodepside, which shows high and broad spectrum of activity.…”

Section: Discussionsupporting

confidence: 88%

“… a Ref . b Ref . c Ref . d Data determined as μg/mL. e Ref . Data in brackets present standard deviations. …”

Section: Results and Discussionmentioning

confidence: 99%

“…The reason the adult gut nematode stages are more sensitive to the macrocyclic lactones has not been studied to date. The activity against S. ratti was variable, the highest activity was observed with ivermectin (IC 50 value: 0.47 μM) . While the drugs lacked activity against H. polygyrus adults (IC 50 values: >100 μM) and low to moderate activity against N. americanus adults (IC 50 values: 39.9–61.2 μM), good activity was observed against adult T. muris (IC 50 values: 10.7–22.9 μM) and even high activity against A. ceylanicum (moxidectin revealing the highest activity of (IC 50 value: <0.01 μM).…”

Section: Results and Discussionmentioning

confidence: 99%

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Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections

Keiser

Häberli

2021

ACS Infect. Dis.

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Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics, albendazole, mebendazole, levamisole, and pyrantel pamoate, for the treatment of soil-transmitted helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight benzimidazoles, five macrocyclic lactones, tribendimidine, levamisole, and pyrantel pamoate in laboratory models of human intestinal nematode infections. In vitro studies were performed on Trichuris muris L1 larval stage and adults, as well as Ancylostoma ceylanicum, Necator americanus, Heligmosomoides polygyrus, and Strongyloides ratti L3 larvae and adults. The benzimidazoles showed pronounced differences against larval and adult stages, with low activity against larvae and the highest activity observed against adult N. americanus (IC 50 of flubendazole 1.1 μM). The macrocyclic lactones, on the other hand, revealed a higher activity on the larval stages, with the lowest IC 50 values observed against N. americanus L3 (IC 50 values of 0.03−3 μM). In vivo studies were performed in the T. muris and H. polygyrus mice models, with moxidectin and milbemycin oxime showing the highest activity against H. polygyrus (ED 50 values of 0.009 and 0.006 mg/kg, respectively) and moxidectin and abamectin being the most effective drugs against T. muris (ED 50 values of 0.2 and 0.5 mg/kg, respectively). Laboratory models for soil-transmitted helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.

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Section: Discussionsupporting

confidence: 88%

“… a Ref . b Ref . c Ref . d Data determined as μg/mL. e Ref . Data in brackets present standard deviations. …”

Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

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Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections

Keiser

Häberli

2021

ACS Infect. Dis.

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“…The larval motility assay is currently the method of choice to evaluate drug sensitivity of different nematode species ( O’Neill et al, 2016 ; Buchter et al, 2021 ). Of all the drugs tested at 50 µM, six (ivermectin, salamectin, moxidectin, pyrantel pamoate, albendazole, and levamisole) were identified to affect the viability of the larvae, and these compounds were further tested at a range of concentrations.…”

Section: Resultsmentioning

confidence: 99%

Susceptibility of Angiostrongylus cantonensis Larvae to Anthelmintic Drugs

et al. 2022

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Human helminthiasis affects approximately one in five people in the world and disproportionally affects the poorest and most deprived communities. Human angiostrongyliasis, caused by nematode Angiostrongylus cantonensis, is a neglected emerging disease with escalating importance worldwide. Chemotherapy is the main control method for helminthiasis, but the therapeutic arsenal is limited. This study aimed to evaluate the antiparasitic and molecular properties of the major available anthelmintic drugs against A. cantonensis in vitro. The first-stage larvae (L1), isolated from feces of an A. cantonensis-infected rat, were exposed to a set of 12 anthelmintic drugs in vitro. The larvae were monitored, and the concentration- and time-dependent viability alterations were determined. From 12 anthelmintic drugs, six (ivermectin, salamectin, moxidectin, pyrantel pamoate, albendazole and levamisole) were identified to affect the viability of A. cantonensis. The macrocyclic lactones (ivermectin, salamectin, moxidectin) and the imidazothiazole levamisole, were the most effective drugs, with IC50 ranging from 2.2 to 2.9 µM and a rapid onset of action. Albendazole, the most widely used anthelmintic in humans, had a slower onset of action, but an IC50 of 11.3 µM was achieved within 24 h. Molecular properties studies suggest that a less lipophilic character and low molecular weight could be favorable for the biological activity of the non-macrocyclic molecules. Collectively, our study revealed that macrocyclic lactones, levamisole, pyrantel pamoate, and albendazole are important anthelmintic agents against A. cantonensis. The results of this in vitro study also suggest that A. cantonensis L1 may be a particularly sensitive and useful model for anthelmintic studies.

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“…Few drugs including moxidectin, emodepside, flubendazole and tribendimidine are currently available and are undergoing various stages of trial as possible alternatives to IVM [21,22]. The aforementioned are all developments from veterinary drugs and are broad-spectrum anthelmintic except emodepside which has a novel mechanism of action, thus cross-resistance between them are likely [21,23].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis

et al. 2021

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Onchocerciasis is the leading cause of blindness and severe skin lesions which remain a major public health problem, especially in tropical areas. The widespread use of antibiotics and the long duration required for effective treatment continues to add to the increasing global menace of multi-resistant pathogens. Onchocerca volvulus harbors the endosymbiont bacteria Wolbachia, essential for the normal development of embryos, larvae and long-term survival of the adult worm, O. volvulus. We report here results of using structure-based drug design (SBDD) approach aimed at identifying potential novel Wolbachia inhibitors from natural products against the Wolbachia surface protein (WSP). The protein sequence of the WSP with UniProtKB identifier Q0RAI4 was used to model the three-dimensional (3D) structure via homology modelling techniques using three different structure-building algorithms implemented in Modeller, I-TASSER and Robetta. Out of the 15 generated models of WSP, one was selected as the most reasonable quality model which had 82, 15.5, 1.9 and 0.5% of the amino acid residues in the most favored regions, additionally allowed regions, generously allowed regions and disallowed regions, respectively, based on the Ramachandran plot. High throughput virtual screening was performed via Autodock Vina with a library comprising 42,883 natural products from African and Chinese databases, including 23 identified anti-Onchocerca inhibitors. The top six compounds comprising ZINC000095913861, ZINC000095486235, ZINC000035941652, NANPDB4566, acetylaleuritolic acid and rhemannic acid had binding energies of −12.7, −11.1, −11.0, −11, −10.3 and −9.5 kcal/mol, respectively. Molecular dynamics simulations including molecular mechanics Poisson-Boltzmann (MMPBSA) calculations reinforced the stability of the ligand-WSP complexes and plausible binding mechanisms. The residues Arg45, Tyr135, Tyr148 and Phe195 were predicted as potential novel critical residues required for ligand binding in pocket 1. Acetylaleuritolic acid and rhemannic acid (lantedene A) have previously been shown to possess anti-onchocercal activity. This warrants the need to evaluate the anti-WSP activity of the identified molecules. The study suggests the exploitation of compounds which target both pockets 1 and 2, by investigating their potential for effective depletion of Wolbachia. These compounds were predicted to possess reasonably good pharmacological profiles with insignificant toxicity and as drug-like. The compounds were computed to possess biological activity including antibacterial, antiparasitic, anthelmintic and anti-rickettsials. The six natural products are potential novel antiwolbachial agents with insignificant toxicities which can be explored further as filaricides for onchocerciasis.

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Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model

Cited by 9 publications

References 31 publications

Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections

Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections

Susceptibility of Angiostrongylus cantonensis Larvae to Anthelmintic Drugs

Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis

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