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The Future Of Parasitology
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2015
Eric S. Loker, Bruce V. Hofkin
Even if we can effectively manage resistance to the drugs currently available, it would be very reassuring to have new drugs at the ready if needed. Continued emphasis should consequently be placed on the development of new categories of anti-parasite drugs. The recent development of compounds such as monepantel, emodepside, and derquantel to treat helminths of sheep and companion animals and spiroindolones to treat malaria are just a few examples. Development of new methods of screening compounds, including compounds already approved for use in other contexts, should be encouraged. Along with this should go ways of retrieving or preserving the usefulness of drugs already available. A significant setback for malaria control was the development of chloroquine resistance in P. falciparum. As noted in Chapter 9 (pages 378–379), this resulted from a mutation in a membrane-associated transporter that enabled malaria parasites to pump chloroquine out of the parasite’s digestive vacuole. Some channel-blocking drugs such as verapamil, by interfering with the mutated transporter protein, interfere with the export of chloroquine, thus potentially restoring its effects. Just one example of the sophisticated and powerful approaches available in the future for retrieving the activity of drugs such as chloroquine, and possibly other drugs to which parasites have developed resistance, is to express the target transporters of parasites in easily manipulated cell types where they can be more easily studied (Figure 10.8).
An Overview of Helminthiasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Leyla Yurttaș, Betül Kaya Çavușoğlu, Derya Osmaniye, Ulviye Acar Çevik
New antihelminthic drugs recently developed are emodepside (17), monepantel (18), derquantel (19), tribendimin (20) and nitazoxanide (21) (Scheme 13). Emodepside (17) is a semi-synthetic derivative obtained from fungus Mycelia sterilia. It was administered in several in vitro and in vivo studies against various nematodes (Olliaro et al. 2011). Monepantel (18) (S-enantiomer) (MOP) is an amino-acetonitrile synthetic derivative. It was discovered in 2008 and approved in the market in 2010. MOP is a broad spectrum antihelminthic active against gastrointestinal nematodes of sheep, including adults and larvae of the most important species. Its effectiveness is determined against nematode strains resistant to benzimidazoles, levamisole, macrocyclic lactones and closantel. MOP has a mode of action based on nematode-specific clade of nicotinic acetylcholine receptor (nAChR) that causes hypercontraction leading to the paralysis and death of adult nematodes (Lecova et al. 2014). Nitazoxanide (21), a salicylic acid derivative, possesses protozoacide, anthelmintic and anti-bacterial properties. It was described previously for cryptosporidiosis and giardiasis, afterwards it was determined that this drug is effective against a number of non-protozoan parasites, including the intestinal tapeworm Hymenolepis nana. Nitazoxanide has variable efficacies against the soil transmitted nematodes, including Ascaris lumbricoides and Trichuris trichiura (Ashour et al. 2016). Derquantel (19) is also a semi-synthetic natural spyroindole derivative produced from Penicillium paraherquei. Because of its short plasma life and efficacy against only fourth stage larvae (L4) of some helminths, it is used in combination with abamectin (Bartram et al. 2012). Tribendimidine (20) is an old molecule which has been recently identified with antinematode activity. Tribendimidine is safe and has good clinical activity against Ascaris and hookworms. It is reported to act as an L-subtype nAChR agonist like levamisole and pyrantel (Hu et al 2019, Dzhafarov and Vasilevich 2014). New antihelminthic drugs recently developed.
Moxidectin: an oral treatment for human onchocerciasis
Published in Expert Review of Anti-infective Therapy, 2020
Philip Milton, Jonathan I. D. Hamley, Martin Walker, María-Gloria Basáñez
The anti-Wolbachia consortium (A·WOL) was established to find anti-Wolbachia drugs at least as efficacious as doxycycline but requiring considerably shorter treatment courses and without its contra-indications [91,92]. Other anti-Wolbachia drugs that have been trialed in humans include rifampicin and moxifloxacin [108] (results yet to be published), and minocycline [109]. Other compounds screened by A∙WOL that have shown great promise in pre-clinical development, are high-dose rifampicin [110], rifampicin plus albendazole [111], and an optimized azaquinazoline (AWZ1066S) [112]. Other compounds (in the Drugs for Neglected Diseases initiative (DNDi) filariasis portfolio) [113] include oxfendazole (for which a phase I trial is being planned through the Helminth Elimination Platform (HELP)), emodepside (nearing phase II trial in Ghana for safety, tolerability, and dose/regimen selection), and TylAMacTM (ABBV-4083, developed by A∙WOL in partnership with AbbVie [114]), for which a phase II proof-of-concept trial is being prepared in the DRC [113].