New advancement in anthelmintic drugs in veterinary medicine

Epe, Christian; Kaminsky, Ronald

doi:10.1016/j.pt.2013.01.001

Cited by 96 publications

(58 citation statements)

References 51 publications

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“…However, spread of resistance is a major problem in the veterinary sector [6]. For treatment of cestode and trematode infections, praziquantel (PZQ) is the drug of choice against most species [7].…”

Section: Introductionmentioning

confidence: 99%

Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds

Ritler¹,

Rufener²,

Sager³

et al. 2017

PLoS Negl Trop Dis

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Intestinal cestodes are infecting millions of people and livestock worldwide, but treatment is mainly based on one drug: praziquantel. The identification of new anti-cestodal compounds is hampered by the lack of suitable screening assays. It is difficult, or even impossible, to evaluate drugs against adult cestodes in vitro due to the fact that these parasites cannot be cultured in microwell plates, and adult and larval stages in most cases represent different organisms in terms of size, morphology, and metabolic requirements. We here present an in vitro-drug screening assay based on Echinococcus multilocularis protoscoleces, which represent precursors of the scolex (hence the anterior part) of the adult tapeworm. This movement-based assay can serve as a model for an adult cestode screen. Protoscoleces are produced in large numbers in Mongolian gerbils and mice, their movement is measured and quantified by image analysis, and active compounds are directly assessed in terms of morphological effects. The use of the 384-well format minimizes the amount of parasites and compounds needed and allows rapid screening of a large number of chemicals. Standard drugs showed the expected dose-dependent effect on movement and morphology of the protoscoleces. Interestingly, praziquantel inhibited movement only partially within 12 h of treatment (at concentrations as high as 100 ppm) and did thus not act parasiticidal, which was also confirmed by trypan blue staining. Enantiomers of praziquantel showed a clear difference in their minimal inhibitory concentration in the motility assay and (R)-(-)-praziquantel was 185 times more active than (S)-(-)-praziquantel. One compound named MMV665807, which was obtained from the open access MMV (Medicines for Malaria Venture) Malaria box, strongly impaired motility and viability of protoscoleces. Corresponding morphological alterations were visualized by scanning electron microscopy, and demonstrated that this compound exhibits a mode of action clearly distinct from praziquantel. Thus, MMV665807 represents an interesting lead for further evaluation.

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Section: Introductionmentioning

confidence: 99%

Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds

Ritler¹,

Rufener²,

Sager³

et al. 2017

PLoS Negl Trop Dis

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“…Emodepside acts at the neuromuscular junction and has a unique mechanism of action relative to other antifilarial drugs, which is not yet fully understood (Harder and von Samson-Himmelstjerna, 2002, Harder et al., 2003, Harder et al., 2005, Willson et al., 2003, von Samson-Himmelstjerna et al., 2005, Krucken et al., 2012, Epe and Kaminsky, 2013, Kulke et al., 2014, Crisford et al., 2015). Pre-clinical pharmacology studies in in-vitro and in-vivo models of human filarial infections, including onchocerciasis models, sponsored in the early 2000s by WHO/TDR showed promising data (WHO/TDR, 2005, Townson et al., 2005).…”

Section: Research For New Drugs For Onchocerciasis Control and Eliminmentioning

confidence: 99%

Research for new drugs for elimination of onchocerciasis in Africa

Kuesel

2016

International Journal for Parasitology: Drugs and Drug Resistan

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Onchocerciasis is a parasitic, vector borne disease caused by the filarial nematode Onchocerca volvulus. More than 99% of the population at risk of infection live in Africa. Onchocerciasis control was initiated in West Africa in 1974 with vector control, later complemented by ivermectin mass drug administration and in the other African endemic countries in 1995 with annual community directed treatment with ivermectin (CDTI.) This has significantly reduced infection prevalence. Together with proof-of-concept for onchocerciasis elimination with annual CDTI from foci in Senegal and Mali, this has resulted in targeting onchocerciasis elimination in selected African countries by 2020 and in 80% of African countries by 2025. The challenges for meeting these targets include the number of endemic countries where conflict has delayed or interrupted control programmes, cross-border foci, potential emergence of parasite strains with low susceptibility to ivermectin and co-endemicity of loiasis, another parasitic vector borne disease, which slows down or prohibits CDTI implementation. Some of these challenges could be addressed with new drugs or drug combinations with a higher effect on Onchocerca volvulus than ivermectin. This paper reviews the path from discovery of new compounds to their qualification for large scale use and the support regulatory authorities provide for development of drugs for neglected tropical diseases. The status of research for new drugs or treatment regimens for onchocerciasis along the path to regulatory approval and qualification for large scale use is reviewed. This research includes new regimens and combinations of ivermectin and albendazole, antibiotics targeting the O. volvulus endosymbiont Wolbachia, flubendazole, moxidectin and emodepside and discovery of new compounds.

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“…Monepantel exerts its action at a new target as a positive allosteric modulator of the nematode specific receptor MPTL-1, which belongs to the DEG-3 subfamily of acetylcholine receptors (Rufener et al, 2010). Monepantel binding to the receptor accounts for an alteration in ion flux and leads to nematode paralysis (Epe and Kaminsky, 2013). This novel mechanism of action explains the high efficacy of monepantel against nematodes resistant to other anthelmintic classes (Baker et al, 2012).…”

Section: Disposition Kinetics and Pharmacodynamic Basis Supporting Momentioning

confidence: 99%

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

Lanusse

Lifschitz

Álvarez

2015

Veterinary Parasitology

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New advancement in anthelmintic drugs in veterinary medicine

Cited by 96 publications

References 51 publications

Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds

Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds

Research for new drugs for elimination of onchocerciasis in Africa

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

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