Insucesso na indução de resistência a drogas esquistossomicidas em uma cepa brasileira humana de Schistosoma mansoni

Dias, Luiz Cândido de Souza; Olivier, Celso Eduardo

doi:10.1590/s0036-46651986000500010

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…Attempts to induce resistance to PZQ1 in the laboratory were reported as early as the 1970s and have continued until the present, mostly focused on S. mansoni (88)(89)(90). Table 4 highlights some of the key studies (from our viewpoint) that attempt to demonstrate the appearance of resistance to PZQ.…”

Section: Experimentally Induced Pzq Resistancementioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

261

218

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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drugresistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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Section: Experimentally Induced Pzq Resistancementioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

261

218

View full text Add to dashboard Cite

show abstract

“…During the first 4 weeks after infection, the parasite is relatively resistant, so that cercariae penetrating <4 weeks prior to treatment will be less affected and continue to develop. In the laboratory, the ability to induce praziquantel resistance has been variable with failures (17, 21) and successes (18, 22, 23). Another confounder in evaluating drug efficacy is evidence that the drug may sterilize, but not kill some parasites (24).…”

Section: Treatment and Resistancementioning

confidence: 99%

Population Structure and Dynamics of Helminthic Infection: Schistosomiasis

Blanton

2019

Microbiol Spectr

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While disease and outbreaks are mainly clonal for bacteria and other asexually reproducing organisms, sexual reproduction in schistosomes and other helminths usually results in unique individuals. For sexually reproducing organisms, the traits conserved in clones will instead be conserved in the group of organisms that tends to breed together, the population. While the same tools are applied to characterize DNA, how results are interpreted can be quite different at times (see Part 4 this series). It is difficult to know what the real effect of any control program has on the parasite population without assessing the health of this population, how they respond to the control measure and how they recover, if they recover. This part of the series "Advances in Molecular Epidemiology of Infectious Diseases" will concentrate on one approach using pooled samples to study schistosome populations and show how this and other approaches have contributed to our understanding of this parasite family's biology and epidemiology. Biology of schistosomes Schistosomiasis is a spectrum of conditions caused by infection with helminthic parasites of the genus Schistosoma. There are seven species that infect humans and three of these are responsible for the bulk of disease: S. mansoni, S. haematobium and S. japonicum. S. mansoni is present in the Americas and much of Africa. S. haematobium is found in Africa and parts of the Middle East, while S. japonicum is transmitted in East Asia. More than 200 million people are infected with one or more of these species, and large outbreaks, even epidemics have occurred in association with major water resource development projects (1). The complex biology of schistosomes distributes their development between a snail host specific to each species of parasite and humans. Other mammalian species may also be infected and maintain transmission, but are generally of less importance with the exception of S. japonicum. A number of domestic and wild animals may be major reservoirs for S. japonicum. The adult parasites inhabit the vascular system where females reside within a groove formed by the male's body to produce 300-3000 eggs per day. Infection produces morbidity by the immune reaction to eggs swept along with the flow of blood back into the liver (S. mansoni and S. japonicum), in the wall of the colon or the urinary system (S. haematobium). Intensity and duration of infection along with host predisposition result in portal hypertension with esophageal varices and bleeding (S. mansoni, S. japonicum) or

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“…This lead us to realize that for the majority of research groups, resistance was considered as achieved when at least 90% of the worm population survived a therapeutic dose. In several studies (Dias and Olivier, 1986; Brindley and Sher, 1987; Brindley et al, 1989; Drescher et al, 1993), various lines of schistosomes did not reach this resistance threshold (with or without induction and/or drug pressure over a couple of generations). They were considered as sensitive although in some cases there was a non-negligible percentage (3–26%) of worms surviving a therapeutic dose of either hycanthone or oxamniquine, strengthening our hypothesis that a mechanism following a non-Mendelian inheritance pattern is involved.…”

Section: Discussionmentioning

confidence: 98%

“…These observations lead us to think that the resistant phenotype in Type II and III could indeed be induced and transmitted to the progeny to a certain extent. Cioli and Pica-Mattoccia (1984), Cioli et al (1989) and Dias and Olivier (1986) stated that they were unable to reproduce Jansma's results in inducing Type II or III resistance. Three other antihelminthics, oxamniquine, praziquantel, and oltipraz were also unsuccessfully tested with the hope of inducing Type II resistance and selecting a new line of resistant schistosomes (Dias and Olivier, 1986).…”

Section: Discussionmentioning

confidence: 99%

Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni

et al. 2014

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Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.

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Insucesso na indução de resistência a drogas esquistossomicidas em uma cepa brasileira humana de Schistosoma mansoni

Cited by 7 publications

References 15 publications

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Population Structure and Dynamics of Helminthic Infection: Schistosomiasis

Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni

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