New approaches for understanding mechanisms of drug resistance in schistosomes

Greenberg, Robert M.

doi:10.1017/s0031182013000231

Cited by 97 publications

(91 citation statements)

References 170 publications

(259 reference statements)

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“…Low drug concentration or, in other words, sublethal PZQ concentration is a hypothesized cause of schistosomal resistance to drug treatment (9). Another considerable concern is that complete dependence on PZQ as the sole drug for treating schistosomiasis may favor the prospects of emerging resistance to the drug (10).…”

mentioning

confidence: 99%

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

El-Feky

Mohamed

Nasr

et al. 2015

Antimicrob Agents Chemother

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c Consideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and its in vivo efficacy against Schistosoma mansoni were investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61-and 1.96-fold and 2.16-and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC 0 -8 ) and maximum concentration of drug in serum (C max ), with a decrease in elimination rate constant (k el ) by 2.84-and 1.35-fold and increases in the absorption rate constant (k a ) and half-life (t 1/2e ) by 2.11-and 1.51-fold and 2.86-and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED 50 ] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ. Schistosomiasis is a parasitic disease caused by blood flukes of the genus Schistosoma and is a serious public health problem in almost 70 countries of the tropics and subtropics without potable water and with poor sanitary conditions. It is estimated that at least 230 million people need treatment against schistosomiasis per year (1). Since an effective vaccine against schistosomiasis is lacking, the emphasis today is placed on the drug praziquantel (PZQ) (2). The low cost has made presumptive treatment on the basis of early clinical symptoms, or even universal treatment, costeffective in many situations (3).Although PZQ has proved to be especially useful in the treatment of schistosomiasis, it sometimes fails to give complete cures in treated populations. The failure of mass treatment to control schistosomiasis has been attributed to the fact that therapy is not sufficiently long-lasting (4). This effect can occur because of the low bioavailability of praziquantel d...

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confidence: 99%

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

El-Feky

Mohamed

Nasr

et al. 2015

Antimicrob Agents Chemother

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“…As a continuation of our development on the (η 6 -PZQ)Cr(CO) 3 derivatives, we present herein the in-depth in vitro metabolic behavior of these chromium derivatives as well as their antischistosomal activity in mice infected with adult S. mansoni. Importantly, we could demonstrate, by preparing optically active (S, Sp)-1, (R, …”

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In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives

Ingram

Leonidova²,

Pierroz³

et al. 2013

J. Med. Chem.

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ABSTRACT. The in vitro metabolic behavior was investigated of two chromium tricarbonyl derivatives of the antischistosomal drug Praziquantel (PZQ) with the formula (η 6 -PZQ)Cr(CO) 3(1 and 2), using human liver microsomes. It could be demonstrated that the metabolic profiles of the derivatives differ significantly. The optically pure (η 6 -PZQ)Cr(CO) 3 derivatives, (S, Sp)-1,were also prepared to assess of the eudysmic ratios of 1 and 2 against S. mansoni. A strong enantioselective antischistosomal activity was observed. The Renantiomers are highly active against adult schistosomes in vitro (IC 50 : 0.08 -0.13 µM) whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic Schistosoma mansoni (S. mansoni) infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24 and 29 % (p>0.05).

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“…The most recent WHO manual for evaluating anthelmintic drug efficacy "tentatively" places the egg reduction rate at approximately 90% for the three main Schistosoma species infecting humans when individuals are treated with 40 mg/kg of PZQ (WHO 2013). On the basis of these criteria, treatment failures with PZQ, although rare, have been reported (Greenberg, 2013) with systematic non-clearers often observed in the field. Warning also comes from veterinary parasitology with anthelminthic resistance an inevitable consequence of mass anthelminthic treatment, with parasites in some regions being resistant to all major drug classes, leading to total anthelminthic failure (Kaplan andVidyashankar, 2012, Webster et al, 2014), and threatening the profitability of whole sheep farming industries in Australia (Wolstenholme et al, 2004).…”

Section: Elucidate the Potential Evolution And Spread Of Praziquantelmentioning

confidence: 99%

Modelling the Effects of Mass Drug Administration on the Molecular Epidemiology of Schistosomes

Lamberton¹,

Crellen²,

Cotton³

et al. 2015

Mathematical Models for Neglected Tropical Diseases: Essential Tools for Control and Elimination, Part A

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New approaches for understanding mechanisms of drug resistance in schistosomes

Cited by 97 publications

References 170 publications

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives

Modelling the Effects of Mass Drug Administration on the Molecular Epidemiology of Schistosomes

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New approaches for understanding mechanisms of drug resistance in schistosomes

Cited by 97 publications

References 170 publications

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η6-Praziquantel)Cr(CO)3 Derivatives

Modelling the Effects of Mass Drug Administration on the Molecular Epidemiology of Schistosomes

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In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives