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      Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

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          Abstract

          Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.

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          Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk.

          An estimated 779 million people are at risk of schistosomiasis, of whom 106 million (13.6%) live in irrigation schemes or in close proximity to large dam reservoirs. We identified 58 studies that examined the relation between water resources development projects and schistosomiasis, primarily in African settings. We present a systematic literature review and meta-analysis with the following objectives: (1) to update at-risk populations of schistosomiasis and number of people infected in endemic countries, and (2) to quantify the risk of water resources development and management on schistosomiasis. Using 35 datasets from 24 African studies, our meta-analysis showed pooled random risk ratios of 2.4 and 2.6 for urinary and intestinal schistosomiasis, respectively, among people living adjacent to dam reservoirs. The risk ratio estimate for studies evaluating the effect of irrigation on urinary schistosomiasis was in the range 0.02-7.3 (summary estimate 1.1) and that on intestinal schistosomiasis in the range 0.49-23.0 (summary estimate 4.7). Geographic stratification showed important spatial differences, idiosyncratic to the type of water resources development. We conclude that the development and management of water resources is an important risk factor for schistosomiasis, and hence strategies to mitigate negative effects should become integral parts in the planning, implementation, and operation of future water projects.
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            Schistosomiasis.

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              Susceptibility or resistance of praziquantel in human schistosomiasis: a review.

              Since praziquantel was developed in 1970s, it has replaced other antischistosomal drugs to become the only drug of choice for treatment of human schistosomiases, due to high efficacy, excellent tolerability, few and transient side effects, simple administration, and competitive cost. Praziquantel-based chemotherapy has been involved in the global control strategy of the disease and led to the control strategy shifting from disease control to morbidity control, which has greatly reduced the prevalence and intensity of infections. Given that the drug has been widely used for morbidity control in endemic areas for more than three decades, the emergence of resistance of Schistosoma to praziquantel under drug selection pressure has been paid much attention. It is possible to induce resistance of Schistosoma mansoni and Schistosoma japonicum to praziquantel in mice under laboratorial conditions, and a reduced susceptibility to praziquantel in the field isolates of S. mansoni has been found in many foci. In addition, there are several schistosomiasis cases caused by Schistosoma haematobium infections in which repeated standard treatment fails to clear the infection. However, in the absence of exact mechanisms of action of praziquantel, the mechanisms of drug resistance in schistosomes remain unclear. The present review mainly demonstrates the evidence of drug resistance in the laboratory and field and the mechanism of praziquantel resistance and proposes some strategies for control of praziquantel resistance in schistosomes.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                05 February 2018
                March 2018
                : 11
                : 1
                : 15
                Affiliations
                [1 ]UCBIO/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo, 228, 4050-313 Porto, Portugal; mariajoaogouveia@ 123456gmail.com
                [2 ]Center for the Study of Animal Science, ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4031-401 Porto, Portugal; jose.costa@ 123456insa.min-saude.pt
                [3 ]Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; fgartner@ 123456ipatimup.pt
                [4 ]Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; pbrindley@ 123456email.gwu.edu
                [5 ]Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
                [6 ]Institute of Investigation and Innovation in Health (i3s), Rua Alfredo Allen, 4200-135 Porto, Portugal
                [7 ]Department of Infectious Diseases, INSA-National Health Institute Dr. Ricardo Jorge, Rua Alexandre Herculano 321, 4000-055 Porto, Portugal
                Author notes
                [* ]Correspondence: nuno.vale@ 123456ff.up.pt ; Tel.: +351-220-428-606
                Article
                pharmaceuticals-11-00015
                10.3390/ph11010015
                5874711
                29401734
                eace3eb3-29e8-462a-8ac3-aebe088ca2b4
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 October 2017
                : 31 January 2018
                Categories
                Review

                schistosomiasis,drug repurposing,praziquantel,antioxidants

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