Anti-schistosomal drugs: observations on the mechanism of drug resistance to hycanthone, and on the involvement of host antibodies in the mode of action of praziquantel

Brindley, Paul J.; Sher, Alan

doi:10.1590/s0074-02761987000800027

Cited by 4 publications

(3 citation statements)

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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%

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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Section: Discussionmentioning

confidence: 98%

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

et al. 2014

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“…It was observed that in B celldeficient mice the schistosomicide effect of PZQ is strongly reduced or completely abolished. The drug efficacy was completely restored by passive transfer of immune serum obtained from S. mansoni infected donor mice at the acute phase [78]. In immunologically intact mice, the efficacy of PZQ can be enhanced by the passive transfer of sera from rabbits immunized with S. mansoni adult worm antigens [79], or by vaccination with a preparation of worm membrane antigens [80].…”

Section: Pzq Mechanism Of Actionmentioning

confidence: 99%

Praziquantel: A Review

Alsaqabi¹

2014

J Veterinar Sci Technol

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Praziquantel (PZQ) History and StructureSystematic searching for schistosomicidal drugs began in the mid-1920s through the work of Kikuth and his colleagues [1][2][3]. Antimonials were the only available chemotherapeutic agents for schistosomiasis from the 1920s to the 1960s. Until the 1970's, treatment of schistosomiasis was nearly as dangerous as the disease itself. New drugs are more consistently effective, less toxic and applicable to oral rather than parenteral administration [4]. During the last decades, niridazole was supplanted by metrifonate for the treatment of infection with S. haematobium and by oxamniquine for S. mansoni but these newer agents have no activity against S. japonicum [5]. Praziquantel (PZQ) is a pyrazinoisoquinoline derivative (Figure 1). The drug name's etymology is p(y)razi(ne) chemical component + qu(inoline) chemical component + ant(h)el(mintic). PZQ was initially synthesized by E. Merck, Germany in the 1970s as potential tranquilizer [6]. Shortly, its anthelminthic properties were tested and proved at the laboratories of Bayer A.G., Germany [7,8]. Praziquantel possesses an asymmetric center in position 11b (arrowhead). The commercial preparation is a mixture of equal parts of levo and dextro-isomers. In vivo and in vitro studies showed that although the two isomers have the same toxicity, only the levo-isomer is responsible for the antischistosomal activity [9][10][11][12]. Half the currently-administered pill is hence unnecessary. A progressive step would be the commercial production of the active enantiomer alone which would reduce to half the amount of drug needed to achieve cure, reduce the tablet size, and allow doses to be increased without compromising safety [13]. Praziquantel was developed first for the veterinary market and then for the human market. Its curative efficacy against various platyhelminths pathogenic to man was confirmed in testing during the 1970s. Early animal studies showed that the drug was about equally effective against S. mansoni, S. hematobium, S. japonicum,

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“…Combining artemether with praziquantel appears to produce a synergistic killing of adult worms [28] . The prospects seem good for prophylaxis with artemether in high-risk groups in areas where schistosomiasis is endemic, such as flood relief workers, tourists and fishermen [29] . The doses required are lower than those required for treatment of malaria, but it is unlikely that artemether would be used in areas where malaria is endemic, because such use might lead to the selection of artemether-resistant Plasmodium falciparum .…”

Section: Treatment Medicalmentioning

confidence: 99%

Parasites of Urological Importance

Kehinde¹,

Anim²,

Hira³

2008

Urol Int

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With the world increasingly becoming a global village, transnational and transcontinental migration has become the order of the day. It is expected that migrants will take with them some diseases (including parasites) which are normally endemic in their countries of origin, to their host countries. Similarly, environmental changes that result from development of water resources, global warming, growth and migration of population can facilitate the spread of parasites. In this review we describe the epidemiology, presentation, diagnosis and treatment options of parasites that urologists may encounter. Notably among these parasites are Schistosoma haematobium, Echinococcus granulosus, Wuchereria bancrofti and Onchocerca volvulus.

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Anti-schistosomal drugs: observations on the mechanism of drug resistance to hycanthone, and on the involvement of host antibodies in the mode of action of praziquantel

Cited by 4 publications

References 0 publications

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

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

Praziquantel: A Review

Parasites of Urological Importance

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