Drugs for treating<i>Schistosoma mansoni</i>infection

Danso‐Appiah, Anthony; Olliaro, Piero; Donegan, Sarah; Sinclair, David; Utzinger, Jürg

doi:10.1002/14651858.cd000528.pub2

Cited by 67 publications

(60 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ability to resolve drug exposure-effect relationships in this study is almost exclusively a function of quantifying drug exposure in terms of AUC 0–24 rather than the reported dose. The extreme PK variability is the likely explanation for the previous observation that better response rates are not observed with given higher dosages (32–34). Overall, higher PZQ dosages than those administered in this study are required to achieve acceptable cure rates (defined as a cure rate of >85%) (3).…”

Section: Discussionmentioning

confidence: 91%

Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy

Bustinduy

Waterhouse

Sousa-Figueiredo

et al. 2016

mBio

View full text Add to dashboard Cite

Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.

show abstract

Section: Discussionmentioning

confidence: 91%

Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy

Bustinduy

Waterhouse

Sousa-Figueiredo

et al. 2016

mBio

View full text Add to dashboard Cite

show abstract

“…Chronic S. mansoni infections cause substantial pathological and physiological changes in infected patients, leading to clinical symptoms such as abdominal pain, diarrhea, blood in the stool, and finally, liver cirrhosis and portal hypertension (18).…”

Section: Discussionmentioning

confidence: 99%

Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

Ingram

Duthaler

Vargas

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cChronic Schistosoma mansoni infections lead to severe tissue destruction of the gut wall and liver and can influence drug disposition. This study aimed to investigate the impact of a chronic S. mansoni infection on the pharmacokinetic (PK) parameters of two promising antischistosomal lead candidates (mefloquine and enpiroline) in mice. Studies were conducted in two different mouse cohorts (S. mansoni-infected and uninfected mice) for both drugs. Plasma samples were collected at various time points after oral treatment (200 mg/kg of body weight) with study drugs. A high-performance liquid chromatography (HPLC) method was validated to analyze enpiroline and mefloquine in plasma. Livers and intestines were collected from infected animals to determine the onset of action, hepatic shift, and worm burden reduction. Following mefloquine administration, hepatic shifting and significant worm burden reductions (79.2%) were observed after 72 h. At 1 week posttreatment with enpiroline, the majority of worms had migrated to the liver and significant worm burden reductions were observed (93.1%). The HPLC method was selective, accurate (87.8 to 111.4%), and precise (<10%) for the analysis of both drugs in plasma samples. The PK profiles revealed increased values for half-life (t 1/2 ) and area under the concentration-time curve (AUC) for both drugs in infected animals compared to the t 1/2 and AUC values in uninfected animals. Considerable changes were observed for mefloquine, with a 5-fold increase of t 1/2 (182.7 h versus 33.6 h) and 2-fold increase of AUC (1,116,517.8 ng · h/ml versus 522,409.1 ng · h/ml). S. mansoni infections in mice influence the PK profiles of enpiroline and mefloquine, leading to delayed clearance. Our data confirm that drug disposition should be carefully studied in schistosomiasis patients.

show abstract

“…Praziquantel (PZQ) is the current drug of choice (Danso-Appiah et al., 2013, Kramer et al., 2013), and is in effect the only antischistosomal treatment currently available (Hagan et al., 2004). Reliance on a single drug for a disease of such high prevalence is a dangerous situation, particularly in light of reports of field and experimentally-induced isolates exhibiting PZQ insusceptibility (reviewed by Day and Botros, 2006, Doenhoff and Pica-Mattoccia, 2006, Greenberg, 2013, Wang et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

TRP channels in schistosomes

Bais

Greenberg

2016

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

Praziquantel (PZQ) is effectively the only drug currently available for treatment and control of schistosomiasis, a disease affecting hundreds of millions of people worldwide. Many anthelmintics, likely including PZQ, target ion channels, membrane protein complexes essential for normal functioning of the neuromusculature and other tissues. Despite this fact, only a few classes of parasitic helminth ion channels have been assessed for their pharmacological properties or for their roles in parasite physiology. One such overlooked group of ion channels is the transient receptor potential (TRP) channel superfamily. TRP channels share a common core structure, but are widely diverse in their activation mechanisms and ion selectivity. They are critical to transducing sensory signals, responding to a wide range of external stimuli. They are also involved in other functions, such as regulating intracellular calcium and organellar ion homeostasis and trafficking. Here, we review current literature on parasitic helminth TRP channels, focusing on those in schistosomes. We discuss the likely roles of these channels in sensory and locomotor activity, including the possible significance of a class of TRP channels (TRPV) that is absent in schistosomes. We also focus on evidence indicating that at least one schistosome TRP channel (SmTRPA) has atypical, TRPV1-like pharmacological sensitivities that could potentially be exploited for future therapeutic targeting.

show abstract

Drugs for treatingSchistosoma mansoniinfection

Abstract: Trusted evidence. Informed decisions. Better health.

Cited by 67 publications

References 118 publications

Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy

Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy

Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

TRP channels in schistosomes

Contact Info

Product

Resources

About