Chlorpromazine, other amphiphilic cationic drugs and praziquantel: effects on carbohydrate metabolism ofSchistosoma mansoni

Harder, Achim; Andrews, P. R.; Thomas, H.

doi:10.1007/bf00578512

Cited by 13 publications

(4 citation statements)

References 16 publications

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“…As yet unpublished work by Harder, Andrews & Thomas (1987 c) on the effects of PZ and fluoxetine on synthetic phospholipid membranes, employed [ 31 P]-NMR-spectroscopy to identify structural membrane changes in relation to ion permeability and drug action, a technique which may lead to a more precise definition of the mode of action of PZ. It is evident from the work of Harder et al (19876) and Harder, Abbink, Andrews & Thomas (1987) on the effects of PZ on schistosome carbohydrate metabolism and comparison with effects of amphiphilic cationic drugs that PZ acts at the membrane level producing a variety of physiological, biochemical and morphological aberrations of normal function.…”

Section: Praziquantelmentioning

confidence: 99%

The interactions between drugs and the parasite surface

Chappell

1988

Parasitology

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SUMMARYThe interrelationships between drugs and parasite surfaces are considered under the headings of (a) effects on membrane transport, (b) drug uptake mechanisms and (c) effects on surface morphology and function: praziquantel is discussed under a separate heading. The range of chemotherapeutic compounds that cause permeability changes and concomitant morphological disruption is discussed in terms of mode of drug action. Interpretation of the available data renders it difficult to identify the primary mode of action in the drugs considered. Drug uptake mechanisms are known for relatively few compounds; drug resistance as a function of drug acquisition is discussed. The role of the parasite surface as a specific drug target is argued.

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Section: Praziquantelmentioning

confidence: 99%

The interactions between drugs and the parasite surface

Chappell

1988

Parasitology

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“…While the five amphiphilic drugs exert a maximal stimulatory effect at concentrations between 10 and 100 μM, PZQ is stimulatory already at 0.1 μM. PZQ is thus much more effective compared to the cationic amphiphilic drugs (Harder et al 1987b ).…”

Section: Pzq Is a Membrane-active Drugmentioning

confidence: 99%

“…Also, the stimulatory effects of serotonin on glucose uptake are completely abolished by PZQ (Harder et al 1987b ). The inhibitory effect of PZQ may be caused by perturbation of the tegument membranes; however, it cannot be excluded that the inhibitory action of PZQ against serotonin-stimulated glucose uptake could rely on a functional antagonistic PZQ action of flatworm 5-HT receptors (Chan et al 2015 ).…”

Section: Pzq Is a Membrane-active Drugmentioning

confidence: 99%

Activation of transient receptor potential channel Sm.(Schistosoma mansoni)TRPMPZQ by PZQ, enhanced Ca++ influx, spastic paralysis, and tegumental disrupture—the deadly cascade in parasitic schistosomes, other trematodes, and cestodes

Harder

2020

Parasitol Res

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After almost 50 years of praziquantel (PZQ) research, Park and Marchant (Trends Parasitol 36:182–194, 2020 ) described the Ca ++ -permeable transient receptor potential (TRP) channel Sm.TRPM PZQ in Schistosoma mansoni as target of PZQ. Here we describe the deadly cascade in schistosomes which is induced by the (R)-PZQ enantiomer that includes contemporaneous stereoselective activation of Sm.TRPM PZQ -mediated Ca ++ influx, disturbed Ca ++ homeostasis, Ca ++ -dependent spastic paralysis, and Ca ++ - and PZQ-dependent disruption of parasitic teguments. Under normal conditions, there is a reversible balance between bilayer, isotropic, and HII phases in biological membranes (Jouhet 2013 ). In vitro, we could observe an irreversible but not stereoselective transition to the HII phase in liposomes consisting of phosphatidylethanolamine (PE) and phosphatidylserine (PS), two naturally occurring phospholipids in schistosomes, by the concerted action of Ca ++ and PZQ (Harder 2013 ). HII structures are a prerequisite for induction of fusion processes (Jouhet 2013 ), which, indeed, become visible as blebs, vacuolation processes, and large balloon-like surface exudates in a large variety of PZQ-sensitive parasitic flukes and cestodes after PZQ treatment. These tegument damages are irreversible. As homologs of Sm.TRPM PZQ are also present in the other trematodes S. japonicum , S. haematobium , or Clonorchis sinensis and cestodes Taenia solium , Echinococcus multilocularis , or Hymenolepis microstoma (Park and Marchant, Trends Parasitol 36:182–194, 2020 ), it is suggested that a similar deadly cascade will be operating generally in PZQ-sensitive parasites.

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“…Secondary effects of PZQ are inhibition of glucose uptake, lowering of glycogen levels and stimulation of lactate release [88,89].…”

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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Chlorpromazine, other amphiphilic cationic drugs and praziquantel: effects on carbohydrate metabolism ofSchistosoma mansoni

Cited by 13 publications

References 16 publications

The interactions between drugs and the parasite surface

The interactions between drugs and the parasite surface

Activation of transient receptor potential channel Sm.(Schistosoma mansoni)TRPMPZQ by PZQ, enhanced Ca++ influx, spastic paralysis, and tegumental disrupture—the deadly cascade in parasitic schistosomes, other trematodes, and cestodes

Praziquantel: A Review

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