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Future Medicinal Chemistry 2015
Topics: Animals; Anthelmintics; Drug Resistance; Humans; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 25996058
DOI: 10.4155/fmc.15.16 -
Bioorganic & Medicinal Chemistry Jul 2017Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a... (Review)
Review
Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study.
Topics: Animals; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neglected Diseases; Oxamniquine; Praziquantel; Schistosoma mansoni; Structure-Activity Relationship
PubMed: 28495384
DOI: 10.1016/j.bmc.2017.04.031 -
The Journal of Antimicrobial... Apr 2014Praziquantel has been the mainstay of schistosomiasis control since 1984 and widely distributed since 2006 through 'preventive chemotherapy' programmes to school-aged... (Review)
Review
Praziquantel has been the mainstay of schistosomiasis control since 1984 and widely distributed since 2006 through 'preventive chemotherapy' programmes to school-aged children or at-risk populations. In addition, preschool-aged children are now recognized as a vulnerable population and a group for targeted treatment, but they may be difficult to dose correctly with the available product--a racemate, based on the biologically active enantiomer (R-praziquantel) and the inactive distomer (S-praziquantel), which contributes the bitter taste and doubles the size of the tablets. Hence, a paediatric formulation is required, possibly enantiomerically pure. Developing such a product and extending its use to younger children should be pharmacologically guided, but limited data exist on pharmacokinetics and pharmacokinetic/pharmacodynamic correlations for praziquantel. This article presents available data on the chemistry, pharmacokinetics and pharmacodynamics of praziquantel, as well as R-praziquantel, and points to gaps in our knowledge.
Topics: Anthelmintics; Humans; Praziquantel; Schistosomiasis; Stereoisomerism
PubMed: 24390933
DOI: 10.1093/jac/dkt491 -
Parasitology Research Nov 2012Since praziquantel was developed in 1970s, it has replaced other antischistosomal drugs to become the only drug of choice for treatment of human schistosomiases, due to... (Review)
Review
Since praziquantel was developed in 1970s, it has replaced other antischistosomal drugs to become the only drug of choice for treatment of human schistosomiases, due to high efficacy, excellent tolerability, few and transient side effects, simple administration, and competitive cost. Praziquantel-based chemotherapy has been involved in the global control strategy of the disease and led to the control strategy shifting from disease control to morbidity control, which has greatly reduced the prevalence and intensity of infections. Given that the drug has been widely used for morbidity control in endemic areas for more than three decades, the emergence of resistance of Schistosoma to praziquantel under drug selection pressure has been paid much attention. It is possible to induce resistance of Schistosoma mansoni and Schistosoma japonicum to praziquantel in mice under laboratorial conditions, and a reduced susceptibility to praziquantel in the field isolates of S. mansoni has been found in many foci. In addition, there are several schistosomiasis cases caused by Schistosoma haematobium infections in which repeated standard treatment fails to clear the infection. However, in the absence of exact mechanisms of action of praziquantel, the mechanisms of drug resistance in schistosomes remain unclear. The present review mainly demonstrates the evidence of drug resistance in the laboratory and field and the mechanism of praziquantel resistance and proposes some strategies for control of praziquantel resistance in schistosomes.
Topics: Animals; Anthelmintics; Disease Models, Animal; Drug Resistance; Humans; Mice; Praziquantel; Schistosoma; Schistosomiasis; Treatment Outcome
PubMed: 23052781
DOI: 10.1007/s00436-012-3151-z -
Expert Review of Anti-infective Therapy Apr 2006Praziquantel became available for the treatment of schistosomiasis and other trematode-inflicted diseases in the 1970s. It was revolutionary because it could be... (Review)
Review
Praziquantel became available for the treatment of schistosomiasis and other trematode-inflicted diseases in the 1970s. It was revolutionary because it could be administered orally and had very few unwanted side effects. As a result of marked reductions in the price of praziquantel, the rate at which it is used has accelerated greatly in recent years. For the foreseeable future it will be the mainstay of programs designed to control schistosome-induced morbidity, particularly in sub-Saharan Africa where schistosomiasis is heavily endemic. There is currently no evidence to suggest that any schistosomes have developed resistance to praziquantel as a result of its widespread use. Nevertheless, while resistance may not pose an obvious or immediate threat to the usefulness of praziquantel, complacency and a failure to monitor developments may have serious consequences in the longer term since it will be the only drug that is readily available for large-scale treatment of schistosomiasis.
Topics: Animals; Anthelmintics; Drug Resistance; Endemic Diseases; Humans; Praziquantel; Schistosomiasis
PubMed: 16597202
DOI: 10.1586/14787210.4.2.199 -
Journal of Enzyme Inhibition and... Dec 2022The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus , except Praziquantel (PZQ), urged to...
The almost empty armamentarium to treat schistosomiasis, a neglected parasitic disorder caused by trematode flatworms of the genus , except Praziquantel (PZQ), urged to find new alternatives to fight this infection. Carbonic Anhydrase from (SmCA) is a possible new target against this nematode. Here, we propose new PZQ derivatives bearing a primary sulphonamide group in order to obtain hybrid drugs. All compounds were evaluated for their inhibition profiles on both humans and Schistosoma CAs, X-ray crystal data of SmCA and hCA II in adduct with some inhibitors were obtained allowing the understanding of the main structural factors responsible of activity. The compounds showed inhibition of immature and adult , but further optimisation is required for improved activity.
Topics: Animals; Carbonic Anhydrases; Humans; Praziquantel; Schistosoma mansoni; Schistosomicides; Sulfanilamide; Sulfonamides
PubMed: 35635137
DOI: 10.1080/14756366.2022.2078970 -
Parasites & Vectors Oct 2011Praziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Praziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the control of this infectious disease since late 1990s. In this article, we conducted a systematic review and meta-analysis to evaluate the antischistosomal efficacy of different medication strategies including monotherapy or combination therapies of these drugs.
RESULTS
A number of 52 trials from 38 articles published in peer-reviewed journals before July 2011 were selected for analysis after searching the following literature databases: the Cochrane Library, PubMed/Medline, ISI Web of Science, Chinese Biomedicine Literature Database, and China National Knowledge Infrastructure. Our meta-analyses showed that a dosage of 30-60 mg/kg praziquantel compared with placebo produced a protection rate of about 76% (95% CI: 67%-83%) for treating human schistosomiasis, which varied from 70% to 76% with no significant differences among the subspecies S. haematobium, S. japonicum or S. mansoni. Protection rates were higher when praziquantel doses were elevated, as concluded from the nRCTs results: the protection rate of praziquantel at 40 mg/kg was 52% (95% CI: 49%-55%), and it increased to 91% (95% CI: 88%-92%) when the dosages were elevated to 60/80/100 mg/kg divided two or more doses. Multiple doses of artemether or artesunate over 1- or 2-week intervals resulted in protection rates of 65% to 97% for preventing schistosomiasis, and increased doses and shorter medication intervals improved their efficacies. Praziquantel and artemisinin derivatives (artemether or artesunate) in combination resulted in a higher protection rate of 84% (95% CI: 64%-91%) than praziquantel monotherapy for treatment. praziquantel and artesunate in combination had a great protection rate of 96% (95% CI: 78%-99%) for preventing schistosomes infection.
CONCLUSIONS
According to the results, praziquantel remains effective in schistosomiasis treatment, and multiple doses would improve its efficacy; meanwhile, praziquantel is also a good drug for preventing acute schistosomiasis morbidity. It's better to use multiple doses of artemether or artesunate with 1- or 2-week intervals for prevention against schistosome infection. Praziquantel and artemether or artesunate in combination perform better in treatment than praziquantel monotherapy, and they are especially suitable for treating the patients with repeated exposure to infected water.
Topics: Animals; Artemisinins; Dose-Response Relationship, Drug; Humans; Praziquantel; Randomized Controlled Trials as Topic; Schistosoma; Schistosomiasis; Schistosomicides
PubMed: 22004571
DOI: 10.1186/1756-3305-4-201 -
PLoS Neglected Tropical Diseases Feb 2024The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by... (Review)
Review
The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resisted identification. However, a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPMPZQ) was recently identified as a target for PZQ action. Here, recent experimental progress interrogating TRPMPZQ is evaluated, encompassing biochemical, pharmacological, genetic, and comparative phylogenetic data that highlight the properties of this ion channel. Various lines of evidence that support TRPMPZQ being the therapeutic target of PZQ are presented, together with additional priorities for further research into the mechanism of action of this important clinical drug.
Topics: Praziquantel; Anthelmintics; Phylogeny; Transient Receptor Potential Channels
PubMed: 38358948
DOI: 10.1371/journal.pntd.0011929 -
Journal of Bioenergetics and... Oct 2020Praziquantel leads to increase Ca influx and disrupts Ca homeostasis in adult Schistosoma. However, calcium influx is only one component in a series of molecular events... (Review)
Review
Praziquantel leads to increase Ca influx and disrupts Ca homeostasis in adult Schistosoma. However, calcium influx is only one component in a series of molecular events leading to the drug effect and some downstream constituents of the cascade that is initiated by this interaction differ between worms with different degrees of susceptibility to praziquantel. Extensive use of the drug raises the concern regarding the selection of drug resistant parasites. SERCA participates in maintenance of Ca homeostasis. Up-regulation of SERCA has been found in Schistosoma mansoni worms with reduced sensitivity to praziquantel. This could be due to increase cytosolic Ca, activation of calmodulin kinase II or may be due to SR/ER stress generated from oxidative stress that leads to impaired protein degradation. The significance of SERCA up-regulation is related to counter action of the drug effect by increasing the worm capacity to restore Ca homeostasis, reducing cytosolic Ca followed by lowering mitochondria Ca and consequently inhibition of apoptosis beside its relation to P-glycoprotein. In schistosomes with reduced sensitivity to praziquantel, the agitations produced by Ca influx and the downstream component of the cascade that is initiated by this interaction may be opposed by up-regulation of SERCA and possibly by certain elements of Ca signaling which modulate the process determining cells entrance in the apoptotic state. Revealing the principal mechanisms of up-regulation of SERCA and its significance in reducing the effect of the drug could lead to possible strategies to reverse drug resistance or develop alternative therapies.
Topics: Animals; Calcium; Endoplasmic Reticulum; Praziquantel; Schistosoma mansoni; Signal Transduction
PubMed: 32557343
DOI: 10.1007/s10863-020-09843-7 -
Trends in Parasitology Mar 2002Praziquantel is currently the drug of choice for the treatment of schistosomiasis. Selective treatment of Schistosoma mansoni infections in various endemic countries... (Review)
Review
Praziquantel is currently the drug of choice for the treatment of schistosomiasis. Selective treatment of Schistosoma mansoni infections in various endemic countries usually present cure rates of >70% when using the standard dose of 40 mg kg(-1) body weight of praziquantel. However, unusually low cure rates (18-38%) have been reported from Senegal, raising fears for emergence of resistance (or tolerance) to praziquantel. One major problem is the precise quantitative interpretation of cure rates, which allows an unequivocal distinction between drug failure and normal drug performance. This article reviews studies on praziquantel treatment of population by standardizing the data through an innovative meta-analysis and provides empirical evidence concerning the extent to which the reported low cure rates from Senegal are atypical.
Topics: Animals; Anthelmintics; Drug Resistance; Humans; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Senegal; Treatment Failure; Treatment Outcome
PubMed: 11854090
DOI: 10.1016/s1471-4922(01)02209-7