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      Efficacy of Cyclooctadepsipeptides and Aminophenylamidines against Larval, Immature and Mature Adult Stages of a Parasitologically Characterized Trichurosis Model in Mice

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          Abstract

          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 (ED 50 values of 6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal treatments (ED 50 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 (ED 50 values of 6.1 vs. 55.7 mg/kg) or subcutaneous (ED 50 values of 15.2 vs. 225.7 mg/kg) administration. Only minimal differences were observed following oral administration (ED 50 values of 2.7 vs. 5.2 mg/kg). Triple and most single oral doses with moderate to high dosages of PF1022A showed complete efficacy against histotropic second stage larvae (3×100 mg/kg or 1×250 mg/kg), further developed larvae (3×10 mg/kg or 1×100 mg/kg) and immature adults (3×10 mg/kg or 1×100 mg/kg). Histotropic first stage larvae were only eliminated after three doses of PF1022A (3×100 mg/kg) but not after a single dose.

          Conclusions/Significance

          These results indicate that the cyclooctadepsipeptides are a drug class with promising candidates for further evaluation for the treatment of trichurosis of humans and livestock animals in single dose regimens.

          Author Summary

          Treatment options against whipworm infections of humans and livestock are very limited and even anthelmintics recently introduced into the market do not significantly improve the situation. Here, we evaluated members of two relatively new drug classes, the aminophenylamidines (amidantel, deacylated amidantel, tribendimidine) and the cyclooctadepsipeptides (PF1022A, emodepside) in a murine trichurosis model. While tribendimidine is licensed for the treatment of human helminthosis caused by hookworms, pinworms and roundworms in China, emodepside is the nematocidal component of dewormers for cats and dogs. With the exception of amidantel, all drugs showed good efficacies against adult whipworms using three consecutive doses. Due to considerations regarding drug safety and price, PF1022A was further evaluated against histotropic first and second stage larvae, further developed larvae, immature and mature adults using a single or three consecutive doses. Three doses eliminated all stages while a single dose was inefficient against histotropic first stage larvae. In general, higher doses were required for early stages in comparison to stages protruding into the gut lumen. Since only a very basic formulation of drugs was tested, further improvement can be expected from optimized formulations. Cyclooctadepsipeptides should therefore be considered as candidates for evaluation to treat Trichuris spp. infections in livestock and humans.

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          Most cited references36

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          The global limits and population at risk of soil-transmitted helminth infections in 2010

          Background Understanding the global limits of transmission of soil-transmitted helminth (STH) species is essential for quantifying the population at-risk and the burden of disease. This paper aims to define these limits on the basis of environmental and socioeconomic factors, and additionally seeks to investigate the effects of urbanisation and economic development on STH transmission, and estimate numbers at-risk of infection with Ascaris lumbricoides, Trichuris trichiura and hookworm in 2010. Methods A total of 4,840 geo-referenced estimates of infection prevalence were abstracted from the Global Atlas of Helminth Infection and related to a range of environmental factors to delineate the biological limits of transmission. The relationship between STH transmission and urbanisation and economic development was investigated using high resolution population surfaces and country-level socioeconomic indicators, respectively. Based on the identified limits, the global population at risk of STH transmission in 2010 was estimated. Results High and low land surface temperature and extremely arid environments were found to limit STH transmission, with differential limits identified for each species. There was evidence that the prevalence of A. lumbricoides and of T. trichiura infection was statistically greater in peri-urban areas compared to urban and rural areas, whilst the prevalence of hookworm was highest in rural areas. At national levels, no clear socioeconomic correlates of transmission were identified, with the exception that little or no infection was observed for countries with a per capita gross domestic product greater than US$ 20,000. Globally in 2010, an estimated 5.3 billion people, including 1.0 billion school-aged children, lived in areas stable for transmission of at least one STH species, with 69% of these individuals living in Asia. A further 143 million (31.1 million school-aged children) lived in areas of unstable transmission for at least one STH species. Conclusions These limits provide the most contemporary, plausible representation of the extent of STH risk globally, and provide an essential basis for estimating the global disease burden due to STH infection.
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            The drugs we have and the drugs we need against major helminth infections.

            Parasitic worms (helminths) have accompanied humans for thousands of years and, still today, they are pervasive where poverty persists, including large parts of Southeast Asia and the Western Pacific Region. The global strategy for the control of helminth infections is morbidity control and elimination as a public health problem. Regular administration of anthelminthic drugs to at-risk populations (e.g. school-aged children) serves as the backbone of interventions in areas where helminth infections are highly endemic. In this review, we focus on soil-transmitted helminthiasis (ascariasis, hookworm disease, strongyloidiasis and trichuriasis) and food-borne trematodiasis (clonorchiasis, fascioliasis, intestinal fluke infections, opisthorchiasis and paragonimiasis) and discuss the few drugs that are currently available for their treatment and control. Emphasis is placed on efficacy with new light shed on multiple dosing and combination therapy. We summarise recent advances made with anthelminthic drugs that might become the future armentarium for the control of major helminthiasis (e.g. artemisinins, cyclooctadepsipeptides, mefloquine, monepantel, nitazoxandide, synthetic peroxides and tribendimidine). Issuing from our review are current research gaps and the need for concerted efforts to discover, develop and deploy the next generation of anthelminthic drugs. Copyright 2010 Elsevier Ltd. All rights reserved.
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              A Research Agenda for Helminth Diseases of Humans: Intervention for Control and Elimination

              Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                February 2014
                20 February 2014
                : 8
                : 2
                : e2698
                Affiliations
                [1 ]Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
                [2 ]Global Drug Discovery – Animal Health – Parasiticides, Bayer HealthCare, Leverkusen, Germany
                [3 ]WE Biology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
                Michigan State University, United States of America
                Author notes

                Daniel Kulke, PhD student of the Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, is employed by Bayer HealthCare, Global Drug Discovery, Animal Health, developing veterinary pharmaceuticals including dewormers. Furthermore, Achim Harder was an employee of Bayer HealthCare when the study was conducted. Except of Achim Harder and Daniel Kulke, Bayer HealthCare was not involved in study design, data collection, data analysis or preparation of the manuscript. The decision to publish the manuscript was jointly taken. This does not alter our adherence to all PLOS policies on sharing data and materials.

                Conceived and designed the experiments: DK AH GvSH. Performed the experiments: DK. Analyzed the data: DK JK. Wrote the paper: DK JK GvSH.

                Article
                PNTD-D-13-01051
                10.1371/journal.pntd.0002698
                3930511
                24587460
                92e2a4a8-f33f-4f55-ad62-24a4b2f987be
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 July 2013
                : 2 January 2014
                Page count
                Pages: 12
                Funding
                The present study was performed as a collaborative research project between Bayer HealthCare and the Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin. Accordingly, the Institute of Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin received a project specific research grant from Bayer HealthCare AG. The funders, except for Achim Harder and Daniel Kulke, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Drugs and devices
                Drug research and development
                Drug discovery
                Infectious diseases
                Neglected tropical diseases
                Trichuriasis
                Parasitic diseases
                Trichuriasis
                Veterinary science
                Veterinary diseases
                Veterinary parasitology
                Parasite physiology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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