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Current Topics in Medicinal Chemistry 2018Despite being one of the most commonly used drugs, the molecular mechanism of action of the anthelmintic praziquantel remains unknown. There are some unusual features of... (Review)
Review
Despite being one of the most commonly used drugs, the molecular mechanism of action of the anthelmintic praziquantel remains unknown. There are some unusual features of this drug. Critically, widespread resistance to praziquantel has not developed despite decades of use. Here, we set out some challenges in praziquantel research and propose some provocative hypotheses to address these. We suggest that praziquantel may have multiple pharmacologically relevant targets and the effects on these may synergise to produce an overall, detrimental effect on the parasite. Praziquantel also acts on a number of host proteins and we propose that these actions are important in the drug's overall mechanism. Although the drug is largely used in the treatment of human and domestic animal worm infections, there is a considerable "grey literature" along with some academic studies which may have been overlooked. It appears that praziquantel may be effective against hydra. It may also be effective against some unicellular parasites such as Giardia spp. Further, scientific work on these understudied areas may be useful in understanding the molecular mechanism in Trematoda. The lack of widespread resistance suggests that praziquantel may act, at least in part, on a protein-protein interaction. Altered drug metabolism or enhanced drug efflux are the most likely ways resistance may arise. There is a critical need to understand the biochemical pharmacology of this drug in order to inform the discovery of the next generation of anthelmintic drugs.
Topics: Animals; Anthelmintics; Giardia lamblia; Humans; Parasitic Sensitivity Tests; Praziquantel; Trematoda
PubMed: 30370849
DOI: 10.2174/1568026618666181029143214 -
Expert Opinion on Therapeutic Patents Sep 2021: Among all the anti-schistosomal drugs, praziquantel has been the most widely used. However, some major challenges have been faced using the drug in the treatment of... (Review)
Review
INTRODUCTION
: Among all the anti-schistosomal drugs, praziquantel has been the most widely used. However, some major challenges have been faced using the drug in the treatment of schistosome infections.
AREAS COVERED
: Several approaches used in the synthesis of praziquantel aimed at reducing the time and cost of production, the toxicity and experimental harsh conditions are discussed. Also, patented methods involved in the pharmaceutical reformulation of praziquantel in the treatment of diverse endoparasitic infestations are reported. Additionally, future perspectives in terms of nanomedicine approach in the formulation of praziquantel are highlighted.
EXPERT OPINION
: Lipid-based nanosystems (LBNSs) formulations can be used to overcome the shortcomings associated with the use of praziquantel in the schistosomiasis treatment due to their amphipathic nature. This could be a promising vehicle for the delivery of praziquantel, which could in turn improve the bioavailability, as well as reduce the frequent dose of the drug and improve patient compliance. This may sustain the release of the drug and improve the rapid conversion of the drug into inactive metabolite due to rapid metabolism. Additionally, LBNSs approach could increase and improve the lipophilicity of the drug, which could make it easier to interact with the hydrophobic cores of the worm tegument.
Topics: Animals; Anthelmintics; Biological Availability; Drug Delivery Systems; Humans; Lipids; Medication Adherence; Nanostructures; Patents as Topic; Praziquantel; Schistosomiasis
PubMed: 33832392
DOI: 10.1080/13543776.2021.1915292 -
International Journal of Pharmaceutics Sep 2023In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely...
In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P2/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M.
Topics: Animals; Mice; Praziquantel; Niclosamide; Antiparasitic Agents; Pharmaceutical Preparations; Spectroscopy, Fourier Transform Infrared; Anthelmintics; Schistosoma mansoni
PubMed: 37579827
DOI: 10.1016/j.ijpharm.2023.123315 -
Pharmacology & Therapeutics 1985
Review
Topics: Animals; Humans; Kinetics; Muscle Contraction; Praziquantel; Schistosoma; Schistosomiasis; Schistosomicides
PubMed: 3914644
DOI: 10.1016/0163-7258(85)90020-8 -
Current Opinion in Pharmacology Oct 2018The commitment to eliminate schistosomiasis as a public health problem has mobilized the expansion of praziquantel treatment to meet the London Declaration targets. New... (Review)
Review
The commitment to eliminate schistosomiasis as a public health problem has mobilized the expansion of praziquantel treatment to meet the London Declaration targets. New research has thus sought to elucidate praziquantel's safety and efficacy in key demographics such as preschoolers and pregnant women, as well as novel elements of its pharmacokinetics and pharmacodynamics. At the same time, reliance on praziquantel ad infinitum would place schistosomiasis control at risk, should resistance occur. In response, the academic community has been filling the pre-clinical drug discovery pipeline with novel or resurrected drug candidates against schistosomiasis. In this review, we highlight the latest research on praziquantel treatment dynamics, which aims to improve the utility of this important drug. Moreover, we present the most promising preclinical antischistosomal candidates, which should be studied further to achieve the ultimate goal- an alternative antischistosomal drug in the near future.
Topics: Drug Discovery; Female; Humans; Praziquantel; Pregnancy; Schistosomiasis; Schistosomicides
PubMed: 30077117
DOI: 10.1016/j.coph.2018.06.004 -
British Journal of Pharmacology Dec 2021The anthelmintic drug praziquantel has been used as a standard treatment for schistosomiasis for over 40 years. This study aimed to repurpose praziquantel to treat...
BACKGROUND AND PURPOSE
The anthelmintic drug praziquantel has been used as a standard treatment for schistosomiasis for over 40 years. This study aimed to repurpose praziquantel to treat psoriasis.
EXPERIMENTAL APPROACH
Psoriasis-like skin inflammation was induced in mice (C57 and Balb/C) by topical application of imiquimod or intradermal injection of recombinant IL-23. Praziquantel was either orally or topically administered during the psoriasis induction period.
KEY RESULTS
Mice treated with either oral or topical praziquantel exhibited markedly improved psoriasiform skin symptoms when compared with control mice, as judged by disease severity score, epidermal thickening, inflammatory cell infiltration and spleen size. Flow cytometric analysis of infiltrating immune cells from mouse skin displayed reduced infiltration of Th17 cells. In vitro experiments revealed that praziquantel inhibited STAT3 phosphorylation and RORγt expression in splenic CD4 T-cells. Praziquantel also decreased STAT3 phosphorylation in HEK-A/F cells. Down-regulation of STAT3 phosphorylation in these cells accounts for the decreased number of Th17 cells and keratinocytes.
CONCLUSION AND IMPLICATIONS
These results provide the first preclinical evidence that praziquantel may effectively treat psoriasis, and suggest that praziquantel alleviates symptoms in mice by inhibiting STAT3 phosphorylation, thereby suppressing Th17 immune responses.
Topics: Animals; Anthelmintics; Disease Models, Animal; Drug Repositioning; Mice; Mice, Inbred BALB C; Praziquantel; Psoriasis; Skin; Th17 Cells
PubMed: 34363611
DOI: 10.1111/bph.15652 -
Mutation Research Dec 1997Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of... (Review)
Review
Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of endpoints including tests in bacteria, yeasts, mammalian cells and Drosophila and each one gave negative results. Effects on reproductive cells of mice were negative as well. However, host mediated studies in mice and humans were contradictory and a comutagenic effect with several mutagens and carcinogens was found. Later studies, including monitoring in humans and pigs have shown that Praziquantel induces a greater frequency of hyperploid lymphocytes as well as structural chromosomal aberrations, but not in all the individuals treated. In vitro studies have demonstrated that Praziquantel can induce micronuclei in syrian hamster embryonic (SHE) cells and in lymphocytes of some individuals. The same was found about structural chromosomal aberrations. Fetal death and fetal resorption were found when Praziquantel was administered in high doses to pregnant rats between the 6th and 10th day of gestation. Due to its efficiency as a parasiticide, Praziquantel is in use in Latin-American, Asiatic, African and East-European countries where infections by trematodes and cestodes are frequent. However, the extensive use of Praziquantel in multiple reinfections, in non-infected and non-diagnosed individuals for prevention, in higher doses or repeated doses for cysticercosis treatment and in individuals exposed to environmental mutagens, in conjunction with new findings about its metabolism and genotoxic properties, make it necessary to further evaluate the potential of this drug not only to be mutagenic per se, but to contribute in the development of neoplasm.
Topics: Animals; Antiplatyhelmintic Agents; Carcinogenicity Tests; Carcinogens; Clinical Trials as Topic; Cricetinae; Cysticercosis; Female; Humans; Mice; Mutagenicity Tests; Mutagens; Praziquantel; Pregnancy; Rats; Schistosomiasis
PubMed: 9439709
DOI: 10.1016/s1383-5742(97)00027-6 -
Trends in Parasitology Feb 2020Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic... (Review)
Review
Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic blood flukes. Treatment of schistosomiasis has relied on a single drug - praziquantel (PZQ) - for decades. The utility of PZQ as an essential medication is, however, intertwined with a stark gap in our knowledge as to how this drug works. No flatworm target has been identified that readily explains how PZQ paralyzes and damages schistosomes. Recently, a schistosome ion channel was discovered that is activated by PZQ and displays characteristics which mirror key features of PZQ action on schistosomes. Here, the journey to discovery of this target, properties of this ion channel, and remaining questions are reviewed.
Topics: Animals; Anthelmintics; Ion Channels; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 31787521
DOI: 10.1016/j.pt.2019.11.002 -
Pediatric Infectious Disease 1983
Topics: Animals; Cestoda; Clonorchis sinensis; Fasciola hepatica; Female; Humans; Isoquinolines; Male; Mammals; Mice; Parasitic Diseases; Praziquantel; Schistosoma
PubMed: 6344048
DOI: 10.1097/00006454-198303000-00018 -
Parasites & Vectors Jan 2017Children carry most of the schistosomiasis burden. While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Children carry most of the schistosomiasis burden. While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited information on efficacy and safety exists for preschool-aged children.
METHODS
Here, we conducted a meta-analysis of clinical trials of praziquantel for treating children with any form of schistosomiasis. Efficacy was reported as cure rate (CR) and egg reduction rates (ERR); statistical corrections were applied based on methodological disparities across trials to derive the predicted geometrical mean ERR (pERRgm). Safety was reported as frequencies of adverse events.
RESULTS
Forty-seven comparative and non-comparative studies were identified, enrolling 15,549 children of whom 14,340 (92%) were assessed between 3 and 8 weeks post-treatment with praziquantel 40 mg/kg (the WHO-recommended treatment, n = 8,380, 56%) or comparators (n = 5,960, 44%). The median age was 10 years (range 1-19), 11% (n = 1,694) were preschool-aged. The CR and pERRgm with praziquantel 40 mg/kg were respectively: S. haematobium, 73.6% (95% CI: 63.5-81.40, 25 study arms) and 94.7% (95% CI: 92.7-96.4); S. mansoni, 76.4% (95% CI: 71.5-81.0, 34 arms) and 95.3% (95% CI: 94.2-96.2); S. mansoni/S. haematobium, 67.6% (95% CI: 54.1-80.7, 5 arms) and 93.4% (95% CI: 89.9-96.2); S. japonicum, 94.7% (95% CI: 92.2-98.0) and 98.7% (95% CI: 98.3-99.2). Mixed-effect multivariate analysis found no significant difference between preschool- and school-aged children for CR or pERRgm in S. haematobium (P = 0.309 and P = 0.490, respectively) or S. mansoni (P = 0.982 and P = 0.895) after controlling for time of assessment, formulation, intensity of infection and detection method. Praziquantel was reportedly safe at all ages, with only mild reported adverse events which cleared rapidly after treatment.
CONCLUSIONS
Praziquantel 40 mg/kg was effective at reducing infection intensity in all Schistosoma species without differences between preschool- and school-aged children. However, conclusions should be tempered because of the limited number of preschool-aged children enrolled, disparities in study procedures and limited information made available in publications, as well as the current imperfect test-of-cure. Also, although reportedly well-tolerated, safety was inconsistently assessed. Studies in target groups, individual-data meta-analysis and standardised methodologies are needed for more robust evidence-base.
Topics: Anthelmintics; Child; Child, Preschool; Female; Humans; Male; Praziquantel; Schistosomiasis
PubMed: 28126024
DOI: 10.1186/s13071-016-1958-7