Schistosomiasis control: keep taking the tablets

Despite the limited reports of praziquantel resistance, the relative success of chemotherapy-based control programmes for schistosomiasis has prompted overdue efforts to expand the use of cheap, generic, praziquantel in sub-Saharan Africa. The likely impact of such programmes on the development and spread of praziquantel resistance is uncertain, but this possibility reinforces the need for monitoring the spectrum of praziquantel sensitivity of schistosome populations and for an improved knowledge of the precise targets for the action of the drug. The search for alternatives to praziquantel and other tools for control of schistosomiasis must continue.     

Schistosome resistance to praziquantel: Fact or artifact?

Praziquantel is the current drug of choice for human schistosomiasis. Recent reports from laboratory and field studies concerning reduced praziquantel efficacy against Schistosoma mansoni have generated some controversy. The prevailing question is whether the emergence of strains of schistosome resistant to praziquantel is a fact, or an artifact resulting from erroneous field or laboratory experimentation. In this article, Padraic Fallon, Liang-feng Tao, Magdi Ismail and James Bennett examine the available evidence for schistosome resistance to praziquantel. Contributory factors to the schistosomicidal activity of praziquantel, which may interfere with evaluation of drug efficacy or resistance, are also considered.     

Interpreting low praziquantel cure rates of Schistosoma mansoni infections in Senegal

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.     

The prophylactic effects of artemether against Schistosoma japonicum infections

The fight against schistosomiasis in China has been very effective in reducing the number of infections across the country. However, the drug of choice, praziquantel, has no prophylactic effect, which reduces its efficacy in high transmission areas. This situation has prompted efforts to find prophylactic compounds, the most promising of which is the drug artemether. In this article, Xiao Shuhua, Mark Booth and Marcel Tanner review the results of laboratory tests and field trials of artemether against schistosomiasis in China.     

Adverse effects of praziquantel treatment of Schistosoma japonicum infection: involvement of host anaphylactic reactions induced by parasite antigen release

The present study using a murine model heavily infected with Schistosoma japonicum aimed to elucidate the pathogenesis of adverse effects of praziquantel treatment of schistosome-infected subjects. Inbred BALB/c mice were infected with S. japonicum (Yamanashi strain) before being treated with a single dose of praziquantel at 4 or 8 weeks p.i. All the mice treated at 8 weeks p.i. exhibited signs typical of systemic anaphylaxis until half of them died shortly after praziquantel administration. At autopsy, these mice exhibited remarkable intestinal alterations characterised by increased mucosal permeability, mucosal oedema and petechial haemorrhage, which are changes typical of immediate intestinal anaphylaxis. In these mice treated at 8 weeks p.i., degranulation of intestinal mast cells was frequently observed, which was particularly remarkable around S. japonicum eggs hatched as an effect of praziquantel. Furthermore, the plasma histamine concentration just after praziquantel treatment was much higher in mice at 8 weeks p.i. than that in uninfected mice or in S. japonicum-infected mice without drug treatment. In contrast, none of these intestinal changes was observed in untreated or uninfected control mice, or in mice administered praziquantel at 4 weeks p.i., in which worm pairs had just reached sexual maturation and begun egg-laying. The finding by ELISA that serum IgM and IgA levels specific to S. japonicum eggs decreased immediately after praziquantel treatment, together with the results of immunohistochemistry, revealed the sudden release of parasite antigens from the eggs hatched by praziquantel treatment. The results of this study demonstrate that adverse effects of praziquantel treatment of schistosomiasis characterised by abdominal signs depend on anaphylactic reactions due to parasite antigens, especially antigens from eggs hatched as an effect of praziquantel.     

A paragonimiasis patient with allergic reaction to praziquantel and resistance to triclabendazole: successful treatment after desensitization to praziquantel

Paragonimiasis is an infectious disease caused by trematodes of the genus Paragonimus. This trematode can be treated successfully with praziquantel in more than 90% of the cases. Although praziquantel is generally well tolerated, anaphylactic reactions to this drug have been reported in a few cases. We report here a 46-year-old Korean female with paragonimiasis, presumed to be due to Paragonimus westermani, who displayed an allergic reaction to praziquantel and resistance to triclabendazole treatment. The patient was successfully treated with praziquantel following a rapid desensitization procedure. Desensitization to praziquantel could be considered when no alternative drugs are available.     

Metabolism of praziquantel in kingfish Seriola lalandi

Investigations into the metabolism of drugs used in aquatic animal therapy are useful for understanding the mechanisms of xenobiotic transformation systems and can aid the development of dosing regimens. This study investigated the metabolism of the synthetic anthelmintic praziquantel, which has application in helminthiasis treatment for several fish species including kingfish Seriola lalandi, a commercial aquaculture finfish species. At least 7 mono- or dihydroxylated derivatives of the parent compound were identified in kingfish after administration of a 150 mg kg(-1) oral praziquantel dose, paralleling findings in mammals. The structure of one representative mono-hydroxylated species that was prominent in the skin, muscle, liver, kidney and plasma of kingfish was investigated using fragmentation experiments; this revealed that hydroxylation of the parent molecule occurred in the tetrahydroisoquinoline region of praziquantel, analogous with mammalian metabolites, but different to that of the active mammalian metabolite (trans-4-OH-praziquantel). The implications of these findings with regard to biotransformation systems for this drug in mammals and fish are discussed.     

Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment

The efficacy of praziquantel against a Puerto Rican strain of Schistosoma mansoni was assessed using both in vivo and in vitro approach. The drug effective dose (50%) in the infected mouse model was about 30 times higher when determined against 28-day-old infections than against 7-week-old parasites. Single-sex female infections were also largely refractory to treatment and single-sex male infections moderately refractory, in comparison with bisexual infections. The in vitro approach consisted of overnight exposure of parasite cultures to various drug concentrations, followed by several days of culture in drug-free medium. In vitro results confirmed in vivo data and allowed for the observation of schistosome morphological phenomena after praziquantel exposure. Early worm contraction was observed in all cases, even after exposure to sub-lethal concentrations of praziquantel or upon exposure of the largely refractory 28-day-old schistosomes. In these instances, however, worms resumed movements and normal shape upon drug removal and were able to survive. The inference of these observations on the clinical use of praziquantel and on its mechanism of action is discussed.     

Hypersensitive reaction to praziquantel in a clonorchiasis patient

Praziquantel is the drug of choice for clonorchiasis. Since clonorchiasis is endemic in most river basins, praziquantel has been widely used for 30 years in Korea. A 54-year-old Korean woman suffered from hypersensitive reactions, such as nausea, dyspnea, rash, and urticaria after taking the first dose of praziquantel to treat clonorchiasis. She ingested one dose again and the same symptoms appeared, and she was treated at a clinic with anti-histamines. She tried one more dose with anti-histamines but found the same symptoms. Later, she was found to pass eggs of Clonorchis sinensis and medicated with flubendazole. The hypersensitive reaction to praziquantel is rare but occurs. This is the 5th case report in the world.     

Treatment of Microcotyle sebastis infestation in cultured rockfish Sebastes schlegeli by oral administration of praziquantel in combination with cimetidine

The effect of cimetidine on the treatment efficacy of praziquantel against Microcotyle sebastis infestation in cultured rockfish Sebastes schlegeli was investigated. Juvenile rockfish were divided into 7 groups, and orally administered praziquantel alone (50, 100 and 200 mg kg(-1) body wt, BW) or in combination with cimetidine at a dose of 200 mg kg(-1) BW for each praziquantel dose. The fish in the control group were administered only saline. The results clearly showed that coadministration of cimetidine with praziquantel led to a significantly increased treatment efficacy of the latter drug, and consequently would lead to a lowering of the total dose of praziquantel, and a reduction in the administration times and costs for the treatment of M. sebastis infestation in cultured rockfish.     

Effect of praziquantel on the immature stages of Schistosoma haematobium

Schistosoma mansoni is known to be refractory to praziquantel treatment in the pre-patent period of infection. Since Schistosoma haematobium has a much longer pre-patent period (10-12 weeks vs. 5-6 for the former species), we asked the question whether a correspondingly longer period of insusceptibility exists in urinary schistosomiasis. In hamsters treated at different times after infection, S. haematobium was partially refractory to praziquantel when treatment was given at week 5, but showed practically full sensitivity at 7-8 weeks and later times. Schistosoma haematobium worms obtained at different times after infection and exposed in vitro to praziquantel were refractory to low drug concentrations between 4 and 6 weeks, but were clearly affected at higher concentrations and at later time points. We conclude that S. haematobium does not have a praziquantel-insensitive window longer than in S. manson, in spite of its much longer maturation period. In addition, refractoriness of immature stages can be overcome at higher drug concentrations.     

Praziquantel adversely affects protoscoleces of Echinococcus granulosus in vitro

Praziquantel was shown to have adverse effects on protoscoleces of Echinococcus granulosus in vitro. Exposure to one dose of praziquantel at a concentration of 10 micrograms/ml caused protoscoleces to die within 12 to 15 days. Protoscolecidal effects were more marked when cultures were exposed to the drug continuously by the addition of multiple doses. On the basis of these observations, there is a need to reappraise the metacestocidal potential of praziquantel, particularly with regard to the development of new drug regimes employing multiple dose or sustained release schedules. Possible reasons for the reduced susceptibility of protoscoleces and juvenile worms to praziquantel observed in this study are discussed.     

Efficacy of praziquantel in treating natural schistosome infections in common mergansers

Fifty-one common mergansers were captured on Douglas Lake (Cheboygan County, Michigan) and their avian schistosome loads were determined by fecal examination. Each bird was given a single dose of 0, 40, or 200 mg/kg of body weight of praziquantel and released. All birds were recaptured within 10 days of drug administration to determine posttreatment schistosome loads. Only the highest dose of praziquantel was found to significantly reduce avian schistosome loads. The potential use of praziquantel in swimmer's itch control programs is discussed.     

Uptake and effect of praziquantel and the major human oxidative metabolite, 4-hydroxypraziquantel, by Schistosoma japonicum

After exposure to praziquantel in vitro at a concentration of 1 microgram/ml for 0.5-2 hr, amounts of praziquantel in Schistosoma japonicum varied from 2.1 +/- 1.2 to 3.7 +/- 1.6 ng/male worm and 1.3 +/- 1.2 to 2.2 +/- 1.5 ng/female worm during the time studied. At 30 micrograms/ml, praziquantel amounts were 11-33-fold higher. However, within 2 hr after removal from a medium containing 30 micrograms/ml praziquantel, 95% of the drug was released from the parasites. When S. japonicum worm pairs were incubated in vitro with 1, 10, and 30 micrograms/ml of 4-hydroxypraziquantel, the major human oxidative metabolite of praziquantel, 0.2 +/- 0.2, 3.8 +/- 1.3, and 7.4 +/- 1.3 ng/worm pair, respectively, were found after a 2-hr incubation. 15-30-fold lower than corresponding worm pair amounts of praziquantel. In vivo, when 4- or 5-wk S. japonicum-infected mice were treated orally with praziquantel (300 mg/kg), peak concentrations of praziquantel in plasma determined by high pressure liquid chromatography were 14.7 +/- 1.5 micrograms/ml (4-wk infection) and 16.7 +/- 2.8 micrograms/ml (5-wk infection) 15 min after treatment. Corresponding in vivo worm praziquantel amounts were 1.8 +/- 0.4 ng/male worm and 2.4 +/- 1.1 ng/female worm, respectively, in the 4-wk infection and 4.6 +/- 1.6 ng/male worm and 5.6 +/- 1.2 ng/female worm in the 5-wk infection. Peak plasma concentrations of 4-hydroxypraziquantel were similar but corresponding in vivo worm amounts were 1-20-fold lower, depending on the time after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of praziquantel has been maintained over four decades (from 1977 to 2018): A systematic review and meta-analysis of factors influence its efficacy

BackgroundThe antihelminthic drug praziquantel has been used as the drug of choice for treating schistosome infection for more than 40 years. Although some epidemiological studies have reported low praziquantel efficacy in cure rate (CR) and/or egg reduction rate (ERR), there is no consistent robust evidence of the development of schistosome resistance to praziquantel (PZQ). There is need to determine factors that lead to variable treatment CR and/or ERR. Therefore, we conducted a systematic review and meta-analysis to review CR and ERR as well as identify their predictors.Methodology/Principal findingsIn this systematic review and meta-analysis, a literature review was conducted using Biosis Citation Index, Data Citation Index, MEDLINE, and Web of Science Core Collection all of which were provided through Web of Science. Alongside these, EMBASE, and CAB abstracts were searched to identify relevant articles. Random effect meta-regression models were used to identify the factors that influence CR and/or ERR by considering differences in host characteristics and drug dose. In total, 12,127 potential articles were screened and 146 eligible articles (published from 1979 to 2020) were identified and included for the meta-analysis. We found that there has been no significant reduction in CR or ERR over the study period. The results showed more variability in CR, compared with ERR which was more consistent and remained high. The results showed a positive effect of “PZQ treatment dose” with the current recommended dose of 40 mg/kg body weight achieving 57% to 88% CR depending on schistosome species, age of participants, and number of parasitological samples used for diagnosis, and ERR of 95%.Conclusions/SignificanceBased on a review of over 40 years of research there is no evidence to support concerns about schistosomes developing resistance to PZQ. These results indicate that PZQ remains effective in treating schistosomiasis.     

The effect of praziquantel on the pseudophyllidean cestode Bothriocephalus acheilognathi in vitro

Adult Bothriocephalus acheilognathi were incubated in solutions containing 0 (control), 0.1, 1.0, 10.0 and 100 micrograms praziquantel per ml (0, 10(2), 10(3), 10(4) and 10(5) micrograms l-1) of 0.9% saline for 5, 15 and 60 min at a temperature of 18 degrees C. The worms contracted immediately upon being placed in the drug. Scanning and transmission electron microscopy revealed considerable tegumental damage particularly in the neck region. Vacuolization and 'bubbling' of the tegument occurred in all of the drug solutions tested. Exposure to drug concentrations of more than 1.0 micrograms ml-1 (10(3) micrograms l-1) praziquantel for 15 min or greater resulted in many of the 'bubbles' bursting and releasing their contents to the exterior. Mature proglottides were distorted and had occasional large swellings resulting in the mass expulsion of eggs. Praziquantel had no ovicidal activity. Exposure to drug concentrations of 100 micrograms (10(5) micrograms l-1) praziquantel per ml saline for 24 h was not lethal to the worms.     

Praziquantel analogs with activity against juvenile Schistosoma mansoni

Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni in infected mice. Only one of these had significant activity against adult worms, but, unlike praziquantel, six of these had low to modest activity against juvenile worms. A praziquantel ketone derivative had the best combination of activity against juveniles and adults, but it had no effect on the motility of adult S. mansoni in ex vivo culture. Cytochrome P450 metabolic stability data support the hypothesis that the major trans-cyclohexanol metabolite of praziquantel plays an important role in the antischistosomal activity of this drug.     

Clinical use of praziquantel in China

Praziquantel, a broad-spectrum anthelmintic developed by E. Merck and Bayer AG in Germany in the early 1970s, was synthesized in the People's Republic of China in 1977 and given the Chinese name Pyquiton. After a series of pharmacological and toxicological studies in China, praziquantel was released for clinical use in 1978. The drug is now available for treatment of human schistosome and other trematode infections as well as the treatment of cestode infections including cysticercosis. However, much of the clinical work has been published in Chinese journals that may not be universally familiar. This article summarizes some of the key aspects of these reports, dealing with the clinical use of praziquantel against schistosomiasis japonica and other helminth infections in China.     

Determination of ED50 values for praziquantel in praziquantel-resistant and -susceptible Schistosoma mansoni isolates

The dose of praziquantel required to kill 50% of adult worms in vivo (i.e. the ED50) was estimated for nine different isolates of Schistosoma mansoni in infected mice. Four of the isolates were selected because they had not knowingly been in contact with the drug (i.e. they were putatively praziquantel-susceptible). Five putatively praziquantel-resistant isolates were chosen because they had been selectively bred for drug-resistance in the laboratory and/or had previously been shown to be relatively resistant to praziquantel in the field. The work was performed in three laboratories in different countries using pre-agreed and comparable experimental protocols. All four praziquantel-susceptible isolates had ED50s estimated to be <100 mg/kg (mean=70+/-7 SD; median=68), while all five putatively praziquantel-resistant isolates had estimated ED50s >100 mg/kg (mean=209+/-48 SD; median=192). Thus, the five praziquantel-resistant isolates, including two that had been subjected to drug pressure during more than 20 passages in mice, had drug ED50s that were approximately three times as great as those of the praziquantel-susceptible isolates. Two of the five isolates in the putatively resistant group had previously been passaged 15 or more times in mice without administration of drug-pressure, but had ED50s consistent with the other three isolates in the group, indicating that the trait of praziquantel-resistance did not necessarily impair biological fitness during laboratory passage. The protocols used here to estimate the praziquantel ED50s of S. mansoni isolates should be useful for establishing and monitoring the drug susceptibility/resistance profiles of parasite isolates freshly obtained from endemic areas, particularly those in which increased usage of the drug is likely to occur.     

Praziquantel and albendazole damaging action on in vitro developing Mesocestoides corti (Platyhelminthes: Cestoda)

Parasitic flatworms present several steps of body architecture rearrangement during their fast transition from one developmental stage to another, which are, at least in part, responsible for their evasion from host immune response. Besides, different developmental stages present different degrees of susceptibility to drug action, and the identification of more susceptible stages is of importance for the definition of therapeutical approaches. Mesocestoides corti (syn. Mesocestoides vogae) is considered a good model to study cestode biology because it can be easily manipulated both in vivo and in vitro and due to its relatively close relationship to cestodes of medical relevance, such as those from genera Echinococcus or Taenia. We have analyzed the damaging action of two broad spectrum anthelmintic drugs (praziquantel and albendazole) throughout the in vitro strobilization process of M. corti in order to identify developmental stages or body structures more susceptible to these drugs. Tetrathyridia (larval stage) and segmented-induced worms were cultivated and treated with praziquantel and albendazole. Whole mounted samples, taken from different developmental stages, were fixed and stained with fluorophore-labeled WGA lectin and phalloidin for the analysis of tegument and muscles, respectively. Confocal laser scanning microscopy was used to identify anatomical changes and lesions caused by each anthelmintic drug in a 3D view. We demonstrated that both praziquantel and albendazole cause extensive tissue damage, especially on tegument, and that adult forms were the most susceptible to drug exposure.