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In vitro and in vivo activity of R- and S- praziquantel enantiomers and the main human metabolite trans-4-hydroxy-praziquantel against Schistosoma haematobium
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In vitro and in vivo activity of R- and S- praziquantel enantiomers and the main human metabolite trans-4-hydroxy-praziquantel against Schistosoma haematobium
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In vitro and in vivo activity of R- and S- praziquantel enantiomers and the main human metabolite trans-4-hydroxy-praziquantel against Schistosoma haematobium
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Journal Article
In vitro and in vivo activity of R- and S- praziquantel enantiomers and the main human metabolite trans-4-hydroxy-praziquantel against Schistosoma haematobium
2017
Overview
Background
Praziquantel (PZQ) is the mainstay of schistosomiasis control and has been successfully used for decades. However, its mechanism of action is not fully understood. While the majority of studies have been conducted on
Schistosoma mansoni
, it is not known which enantiomer, R- or S-praziquantel (R-/S-PZQ), is responsible for the activity on
Schistosoma haematobium
.
Methods
In vitro and in vivo studies were conducted to evaluate the activity of R- and S-PZQ, racemic PZQ and the main human metabolite, namely
trans
-4-OH-PZQ, on
S. haematobium
. IC
50
values on adult
S. haematobium
were determined in vitro. Dose-response relationship studies were performed in golden Syrian hamsters, harbouring a chronic
S. haematobium
infection.
Results
R-PZQ displayed the highest activity against adult worms in vitro, revealing an IC
50
of 0.007 μg/ml at 4 h and 0.01 μg/ml at 72 h. In contrast, S-PZQ was 501× less active (eudysmic ratio at 4 h), with an IC
50
of 3.51 and 3.40 μg/ml (4 and 72 h, respectively). Racemic PZQ and
trans
-4-OH-PZQ resulted in an IC
50
of 0.03 μg/ml and 1.47 μg/ml both at 4 and 72 h, respectively. In vivo, R-PZQ was the most potent drug with worm burden reductions (WBRs) of 98.5, 75.6 and 73.3% at 125.0, 62.5 and 31.0 mg/kg, respectively. A single oral dose of 250.0 mg/kg PZQ resulted in a WBR of 99.3%. S-PZQ was highly active in vivo at 250.0 and 500.0 mg/kg with WBRs of 83.0 and 94.1%, respectively. The lowest tested dose of S-PZQ, 125.0 mg/kg, showed moderate activity (WBR of 46.7%). The calculated ED
50
for R- and S-PZQ were 24.7 and 127.6 mg/kg, respectively, with a corresponding eudysmic ratio of 5.17.
Conclusion
Our data support the theory of R-PZQ driving the antischistosomal activity. Interestingly, also S-PZQ proved to possess a significant activity towards
S. haematobium
, particularly in vivo.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Animals
/ Biomedical and Life Sciences
/ Drugs
/ Hamsters
/ Humans
/ In vitro
/ In vivo
/ Male
/ Motility
/ Praziquantel - analogs & derivatives
/ Praziquantel - therapeutic use
/ Schistosoma haematobium - drug effects
/ Schistosoma mansoni - drug effects
/ Schistosomiasis haematobia - drug therapy
/ Schistosomiasis haematobia - parasitology
/ Schistosomiasis mansoni - drug therapy
/ Schistosomicides - metabolism
/ Schistosomicides - pharmacology
/ Schistosomicides - therapeutic use
/ Structure-activity relationships (Pharmacology)
/ Studies
/ Testing
/ Veterinary Medicine/Veterinary Science
/ Virology
/ Worms
