Date Published: January 13, 2009
Publisher: Public Library of Science
Author(s): Thorsten Meyer, Harald Sekljic, Stefan Fuchs, Heiko Bothe, Dieter Schollmeyer, Christian Miculka, Donato Cioli
Abstract: BackgroundPraziquantel (PZQ) is the drug compound of choice in the control and treatment of schistosomiasis. PZQ is administered as a racemate, i. e. 1∶1 mixture of enantiomers. The schistosomicidal activity arises from one PZQ-enantiomer, whereas the other enantiomer does not contribute to the activity. The WHO’s Special Programme for Research and Training in Tropical Diseases (TDR) has assigned the low-cost preparation of pure schistosomicidal (−)-PZQ a key priority for future R&D on PZQ, but so far this transition has not happened. PZQ has two major administration drawbacks, the first being the high dose needed, and its well documented bitter and disgusting taste. Attempts of taste-masking by low-cost means have not been successful. We hypothesized that the non-schistosomicidal component in PZQ would be the main contributor to the unpleasant taste of the drug. If the hypothesis was confirmed, the two major administration drawbacks of PZQ, the high dose needed and its bitter taste, could be addressed in one go by removing the component contributing to the bitter taste.Methods and FindingsPZQ was separated into its schistosomicidal and the non-schistosomicidal component, the absolute stereochemical configuration of (−)-PZQ was determined to be (R)-PZQ by X-ray crystallography, and the extent of bitterness was determined for regular racemic PZQ and the schistosomicidal component in a taste study in humans. Finding: The schistosomicidal component alone is significantly less bitter than regular, racemic PZQ.ConclusionOur hypothesis is confirmed. We propose to use only the pure schistosomicidal component of PZQ, offering the advantage of halving the dose and expectedly improving the compliance due to the removal of the bitter taste. Therefore, (R)-PZQ should be specifically suitable for the treatment of school-age children against schistosomiasis. With this finding, we would like to offer an additional incentive to the TDR’s recommendation to switch to the pure schistosomicidal (R)-PZQ.
Partial Text: Praziquantel  (PZQ) is the drug compound of choice in the control and treatment of schistosomiasis , in fact, it is the only commercially readily available drug. So far, no backup compound for PZQ of comparable efficacy and breadth of application is available. Clinically relevant resistance has not been observed, however differences in responses of PZQ-resistant and -susceptible Schistosoma mansoni to PZQ in vitro have been described . PZQ is included in the WHO Model List of Essential Drugs  and is at the core of numerous schistosomiasis control programmes. The WHO’s strategy for schistosomiasis control  aims at reducing morbidity through treatment with PZQ, with a focus on periodic treatment of school-age children and adults considered to be at risk. School-age children are seen as a high-risk group for schistosome infections because they are more susceptible to infection in cases where their increased nutritional needs are not adequately met, might be compromised by helminth infections in their cognitive development, and are continuously exposed to contaminated soil and water but probably less aware of the need for good personal hygiene .
The results of the determination of bitterness values are shown in Table 1. Remarkable is the variation of the individuals’ results as indicated by the relative standard deviation and the dispersion of the results in the box-and-whisker diagram (Figure 3). In contrast to the average, the medians of the results, as depicted in the box-and-whisker diagram, are different from each other. The observed variation was probably provoked by the test panel consisting of untrained members only . Thirteen out of fifteen panel members found (R)-PZQ to taste less bitter than racemic PZQ. Although no statistical test is required or proposed by the European Pharmacopoeia, a statistical test (using SAS software, release 9.1.3, SAS Institute Inc., Cary, NC, USA) was conducted to investigate the observed difference between the compounds. Considering the small sample size and the nature of the data which does not justify the assumption of a normal distribution, a nonparametric, distribution-free method was chosen. On the 5% level of significance, Wilcoxon’s Signed Rank Test (two-sided) resulted in a significant difference between the taste of racemic PZQ and (R)-PZQ (p = 0.0107). This result was confirmed by the Sign Test (two-sided, p = 0.0018).
The schistosomicidal component of regular PZQ, (R)-PZQ has a less unpleasant taste compared to racemic PZQ, which was found to be comparably bitter or unpleasant. It can be assumed that the disgusting taste of racemic PZQ stems from the non-schistosomicidal component, (S)-PZQ. Removing the latter from currently used racemic PZQ therefore not only offers the chance to halve the dose, with the potential to decrease the number or size of the tablets, but also addresses the second disadvantage of regular, racemic PZQ-its unpleasant taste. With this finding and its publication we would like to offer an additional incentive to focus work of the PZQ R&D community on further decreasing the cost of production of (R)-PZQ with the goal to switch to pure (R)-PZQ as a replacement for racemic PZQ for the treatment of school-age children against schistosomiasis.