Chemotherapy for human schistosomiasis: how far have we come? What's new? Where do we go from here?

Dziwornu, Godwin Akpeko; Attram, Henrietta Dede; Gachuhi, Samuel; Chibale, Kelly

doi:10.1039/d0md00062k

Cited by 13 publications

(18 citation statements)

References 167 publications

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“…Praziquantel (PZQ) is an anthelmintic drug widely used in developing countries to treat schistosomiasis, a neglected tropical disease caused by parasitic blood flukes of the Schistosoma genus. 1 Approximately 800 million people are at risk of schistosomiasis and around 250 million are infected, with a high prevalence in the pediatric population. 2 The fluke infection causes chronic immunogenic inflammatory, granulomatous, and fibrotic reactions, accompanied with several functional morbidities that impair normal physiological functioning and growth of an infected child.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

et al. 2021

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Praziquantel (PZQ) is a biopharmaceutical classification system (BCS) class II anthelmintic drug characterized by poor solubility and a bitter taste, both of which can be addressed by inclusion complexation with cyclodextrins (CD). In this work, a comprehensive investigation of praziquantel/cyclodextrin (PZQ/CD) complexes was conducted by means of UV–vis spectroscopy, spectrofluorimetry, NMR spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS), and molecular modeling. Phase solubility studies revealed that among four CDs tested, the randomly methylated β-CD (RMβCD) and the sulfobutylether sodium salt β-CD (SBEβCD) resulted in the highest increase in PZQ solubility (approximately 16-fold). The formation of 1:1 inclusion complexes was confirmed by HRMS, NMR, and molecular modeling. Both cyclohexane and the central pyrazino ring, as well as an aromatic part of PZQ are included in the CD central cavity through several different binding modes, which exist simultaneously. Furthermore, the influence of CDs on PZQ stability was investigated in solution (HCl, NaOH, H 2 O 2 ) and in the solid state (accelerated degradation, photostability) by ultra-high-performance liquid chromatography–diode array detection–tandem mass spectrometry (UPLC-DAD/MS). CD complexation promoted new degradation pathways of the drug. In addition to three already known PZQ degradants, seven new degradation products were identified ( m / z 148, 215, 217, 301, 327, 343, and 378) and their structures were proposed based on HRMS/MS data. Solid complexes were prepared by mechanochemical activation, a solvent-free and ecologically acceptable method.

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Section: Introductionmentioning

confidence: 99%

“… 2 PZQ is included in the World Health Organization List of Essential Medicines for treatments of adults and children as it has good efficiency, a favorable safety profile, and low production costs. 1 …”

Section: Introductionmentioning

confidence: 99%

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

et al. 2021

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“…This paper documents the discovery of a potent series of anti-schistosomiasis compounds with excellent prospects for achieving a single dose cure in humans that stand out from those reported in a recent extensive review of the field [17] and series reported since that review [29][30][31]. The weakly potent original hits have been optimised to compounds with approximately three orders of magnitude better in vitro potency.…”

Section: Discussionmentioning

confidence: 99%

“…These include development and application of whole organism screens for compound testing [14], target-based drug discovery [15] and identification of putative molecular targets by analysis of the annotated schistosome genome sequences [16]. A recent comprehensive review of compounds with schistosomicidal activity [17] demonstrates the relative lack of promising series in the area.…”

Section: Introductionmentioning

confidence: 99%

The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species

Gardner¹,

Mansour

Bell³

et al. 2021

PLoS Negl Trop Dis

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Treatment and control of schistosomiasis depends on a single drug, praziquantel, but this is not ideal for several reasons including lack of potency against the juvenile stage of the parasite, dose size, and risk of resistance. We have optimised the properties of a series of compounds we discovered through high throughput screening and have designed candidates for clinical development. The best compounds demonstrate clearance of both juvenile and adult S. mansoni worms in a mouse model of infection from a single oral dose of < 10 mg/kg. Several compounds in the series are predicted to treat schistosomiasis in humans across a range of species with a single oral dose of less than 5 mg/kg.

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“…A reliable diagnostic method is microscopic detection of eggs in urine, feces, or tissue biopsy together with the detection of specific antibodies, e.g., by ELISA; less frequently, detection of parasitic DNA and RNA by PCR is done [4,5]. Effective peroral medication with praziquantel (PZQ) and oxamniquine (OXA) is available; the mechanism of their action is not known in detail [6]. Human infection occurs mainly after exposure in natural freshwater res Acute and chronic schistosomiasis may be recognized.…”

Section: Introduction 1genus Schistosomamentioning

confidence: 99%

Inactivation of Schistosoma Using Low-Temperature Plasma

et al. 2020

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The inactivation of Schistosoma mansoni cercariae and miracidia was achieved by exposure to plasma produced by the positive, negative, and axial negative corona discharges. The positive discharge appeared as the most effective, causing the death of cercariae and miracidia within 2–3 min of exposure. The negative discharge was less effective, and the axial discharge was ineffective. The water pre-activated (PAW) by the discharges showed similar efficiency, with the exception of the significantly effective PAW activated with axial discharge. These facts, together with the observation of various reactions among plasma-damaged schistosomes, suggest that the mechanisms of inactivation by different types of discharges are different.

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Chemotherapy for human schistosomiasis: how far have we come? What's new? Where do we go from here?

Abstract: After a century since the first antimonial-based drugs were introduced to treat the disease, anti-schistosomiasis drug development is again at a bottleneck with only one drug, praziquantel, available for treatment purposes.

Cited by 13 publications

References 167 publications

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species

Inactivation of Schistosoma Using Low-Temperature Plasma

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