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Aim: The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects., Methods: Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment., Results: The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and C max (α = 0.05). The geometric mean ratios of the AUC and C max were found to be 176.8% and 227% respectively. The 90% CI of the AUC and C max were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration., Conclusions: The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.

Background: Elimination of schistosomiasis as a public health problem and interruption of transmission in selected areas are targets set by WHO for 2025. Our aim was to assess biannual mass drug administration (MDA) applied alone or with complementary snail control or behaviour change interventions for the reduction of Schistosoma haematobium prevalence and infection intensity in children from Zanzibar and to compare the effect between the clusters., Methods: In a 5-year repeated cross-sectional cluster-randomised trial, 90 shehias (small administrative regions; clusters) in Zanzibar eligible owing to available natural open freshwater bodies and public primary schools were randomly allocated (ratio 1:1:1) to receive one of three interventions: biannual MDA with praziquantel alone (arm 1) or in combination with snail control (arm 2), or behaviour change activities (arm 3). Neither participants nor field or laboratory personnel were blinded to the intervention arms. From 2012 to 2017, annually, a single urine sample was collected from approximately 100 children aged 9-12 years in the main public primary school of each shehia. The primary outcome was S haematobium infection prevalence and intensity in 9-12-year-old children after 5 years of follow-up. This study is completed and was registered with the ISRCTN, number 48837681., Findings: The trial was done from Nov 1, 2011, through to Dec 31, 2017 and recruitment took place from Nov 2, 2011, until May 17, 2017. At baseline we enrolled 8278 participants, of whom 2899 (35%) were randomly allocated to arm 1, 2741 (33%) to arm 2, and 2638 (32%) to arm 3. 120 (4·2%) of 2853 in arm 1, 209 (7·8%) of 2688 in arm 2, and 167 (6·4%) of 2613 in arm 3 had S haematobium infections at baseline. Heavy infections (≥50 eggs per 10 mL of urine) were found in 126 (1·6%) of 8073 children at baseline. At the 5-year endline survey, 46 (1·4%) of 3184 in arm 1, 56 (1·7%) of 3217 (odds ratio [OR] 1·2 [95% CI 0·6-2·7] vs arm 1) in arm 2, and 58 (1·9%) of 3080 (1·3 [0·6-2·9]) in arm 3 had S haematobium infections. Heavy infections were detected in 33 (0·3%) of 9462 children., Interpretation: Biannual MDA substantially reduced the S haematobium prevalence and infection intensity but was insufficient to interrupt transmission. Although snail control or behaviour change activities did not significantly boost the effect of MDA in our study, they might enhance interruption of transmission when tailored to focal endemicity and applied for a longer period. It is now necessary to focus on reducing prevalence in remaining hotspot areas and to introduce new methods of surveillance and public health response so that the important gains can be maintained and advanced., Funding: University of Georgia Research Foundation Inc and Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Schistosomiasis is a chronic debilitating parasitic disease that causes hepatic damage and is known to be endemic in developing countries. Recent control strategies for schistosomiasis depend exclusively on chemotherapeutic agents, specifically praziquantel. Unfortunately, praziquantel has low efficacy in the early phase of infection, and resistance to treatment is increasingly reported. The aim of this work was to find an alternative treatment by assessing the in vivo activity of aqueous extract of Callistemon citrinus against Schistosoma mansoni in both prepatent and patent phases in experimentally infected mice. The study was conducted on 80 male BALB/c albino mice divided into eight groups. Callistemon was administered at a dose of 200 mg/kg on days 14 and 45 post infection as a single therapy and in combination with praziquantel. Porto-mesenteric worm burden, hepatic and intestinal egg counts, hepatic granuloma number and diameter, and oogram pattern were assessed to evaluate the anti-schistosomal properties of C. citrinus. Liver enzymes and total bilirubin were tested to assess hepatoprotective effects. Results revealed that the use of C. citrinus was associated with a significant decrease in worm burden and tissue egg load together with an increased percentage of dead eggs. In addition, there was a significant reduction in granuloma formation. Callistemon also led to a significant improvement in liver function. The best results were obtained when C. citrinus was given in the prepatent phase of infection and when combined with praziquantel. Although the effects of C. citrinus are considered to be promising, further studies using different extracts, active ingredients and doses are needed.

Schistosomiasis is a blood parasitic disease caused by trematode parasites of the genus Schistosoma . Schistosoma mansoni is one of the main contributors of the disease and 90% of the global burden of schistosomiasis is in Africa. Mass drug administration (MDA) has been implemented to reduce the disease burden in endemic areas. Because of MDA, the diagnostic sensitivity and specificity for classical diagnostic tests are reduced. In any disease situation, diagnosis is vital in determining asymptomatic, concurrent, current, new, and reinfection cases to evaluate the efficacy of any control program. We have evaluated the positive infection for S. mansoni from filtered urine samples collected from Zambian school children after MDA using loop-mediated isothermal amplification (LAMP) and compared its sensitivity and specificity with polymerase chain reaction (PCR). One hundred eleven urine samples collected from school children aged between 7 and 15 years from Siavonga district in southern Zambia were evaluated by PCR and LAMP for DNA extracted by two different protocols (filter-based versus crude extraction). The infection prevalence was 77% with PCR and almost 94% with mansoni-LAMP. Also, LAMP detected 16% (Qiagen extraction) and 10% (LAMP-Procedure for Ultra Rapid Extraction) more positive S. mansoni infection than PCR. We have demonstrated the efficacy of LAMP in a laboratory setup after MDA. The possible inclusion of LAMP as a field-based point-of-care test for surveillance can provide reliable prevalence of schistosomiasis after MDA and help in determining the efficacy of a control program.

Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug's bioavailability in the presence of glycyrrhizin.

Background: The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment., Methods/findings: This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12-16 weeks' gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks' gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated., Conclusions: Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface., Clinical Trial Registry Number and Website: ClinicalTrials.gov (NCT00486863)., Competing Interests: The authors have declared that no competing interests exist.

Forty-four Schistosoma mansoni egg-negative/circulating cathodic antigen (CCA) low-positive (trace or 1+) children in three districts of very low prevalence in Egypt were given three sequential praziquantel (PZQ) treatments. Stool and urine specimens were collected 3 months following the initial treatment, and 3 weeks following the second and following the third PZQ treatments, which were conducted 5 weeks apart. Stool specimens were examined by Kato-Katz (four slides/stool sample) and all S. mansoni egg-negative stools were further tested by the "miracidia hatching test" (MHT). Urine samples were examined by the point-of-care CCA assay (POC-CCA). Over the study period, all stool samples from study subjects remained S. mansoni egg negative and MHT negative. Of the POC-CCA test results, in the first day of the study 3 months following the initial treatment, 29.5% were negative, 61.4% CCA trace positives, and 9.1% CCA 1+ positives. Following each PZQ treatment, the test results fluctuated between 1+, trace, and negative, but did not consistently decrease. The proportions of POC-CCA-positive results obtained in the first day (70.5%) as compared with the last day of the study (72.7%) in all of the three districts were very similar. We conclude that CCA trace and 1+ readings, in Kato-Katz S. mansoni egg-negative children in this area with very low levels of intestinal schistosomiasis, are not consistently altered or rendered consistently negative following repeated PZQ treatments and are therefore likely to represent false-positive readings. This finding is of critical importance for countries such as Egypt as they approach elimination.

The purpose of this study was 2-fold: 1) to investigate the prevalence of gastrointestinal parasite infection in cats reared in Daegu, Republic of Korea and 2) to assess the efficacy and safety of a topical emodepside/praziquantel formulation for cats with parasitic infections. The gastrointestinal parasite infections were examined microscopically using the flotation method. Of 407 cats, 162 (39.8%) were infected by at least one gastrointestinal parasite, including Toxocara cati (63.0%), Toxascaris leonina (31.5%), Taenia taeniaeformis (3.7%), and Cystoisospora felis (1.9%). None of the infected animals had multiple infections. When the data were analyzed according to sex, age, and type of cat, stray cats showed statistically higher prevalence than companion cats (P&lt;0.05). On the 5th day after treatment, no parasitic eggs were detected using microscopic examination. In addition, no adverse effects, such as abnormal behaviors and clinical symptoms, were observed in the cats treated with the drug. These results quantify the prevalence of gastrointestinal parasites in cats in Daegu, Republic of Korea, and show that topical emodepside/praziquantel is a safe and effective choice for treating the parasitic infections in cats.

Background: The Zanzibar Elimination of Schistosomiasis Transmission (ZEST) project aimed to eliminate urogenital schistosomiasis as a public health problem from Pemba and to interrupt Schistosoma haematobium transmission from Unguja in 5 years., Methodology: A repeated cross-sectional cluster-randomized trial was implemented from 2011/12 till 2017. On each island, 45 shehias were randomly assigned to receive one of three interventions: biannual mass drug administration (MDA) with praziquantel alone, or in combination with snail control or behavior change measures. In cross-sectional surveys, a single urine sample was collected from ~9,000 students aged 9- to 12-years and from ~4,500 adults aged 20- to 55-years annually, and from ~9,000 1st year students at baseline and the final survey. Each sample was examined for S. haematobium eggs by a single urine filtration. Prevalence and infection intensity were determined. Odds of infection were compared between the intervention arms., Principal Findings: Prevalence was reduced from 6.1% (95% confidence interval (CI): 4.5%-7.6%) to 1.7% (95% CI: 1.2%-2.2%) in 9- to 12-year old students, from 3.9% (95% CI: 2.8%-5.0%) to 1.5% (95% CI: 1.0%-2.0%) in adults, and from 8.8% (95% CI: 6.5%-11.2%) to 2.6% (95% CI: 1.7%-3.5%) in 1st year students from 2011/12 to 2017. In 2017, heavy infection intensities occurred in 0.4% of 9- to 12-year old students, 0.1% of adults, and 0.8% of 1st year students. Considering 1st year students in 2017, 13/45 schools in Pemba and 4/45 schools in Unguja had heavy infection intensities >1%. There was no significant difference in prevalence between the intervention arms in any study group and year., Conclusions/significance: Urogenital schistosomiasis was eliminated as public health problem from most sites in Pemba and Unguja. Prevalence was significantly reduced, but transmission was not interrupted. Continued interventions that are adaptive and tailored to the micro-epidemiology of S. haematobium in Zanzibar are needed to sustain and advance the gains made by ZEST., Competing Interests: The World Health Organization donated praziquantel to cover biannual mass drug administration conducted by the Neglected Diseases Program of the Zanzibar Ministry of Health, the Schistosomiasis Control Initiative funded the treatment implementation across Zanzibar, and Bayer S.A.S. donated 3 MT Bayluscide for snail control for use in the project.

Background: Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. Although PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. A hybrid drug containing different pharmacophores within a single molecule is a promising strategy. Our earlier in vivo studies showed the significant antiparasitic activity of a praziquantel derivative, DW-3-15, against Schistosoma japonicum. In the present study, DW-3-15 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro. An in vivo study was conducted to assess the effect of commercial DW-3-15 on worm burden, egg production and diameter of granulomas. Additionally, to gain insight into the mechanism of action for DW-3-15, morphological changes in the tegument of S. japonicum were also examined., Results: The in vitro study showed the antiparasitic activity of DW-3-15 against S. japonicum, with significant reductions in viability of adult and juvenile worms, worm pairings and egg output. Compared to PZQ, DW-3-15 induced similar ultrastructural changes and evident destruction of the tegument surface in male worms. In vivo, the oral administration of DW-3-15 at a dose of 400 mg/kg per day for five consecutive days in mice significantly reduced the total worm burden and number of eggs in the liver. Histological analysis of the livers showed a marked reduction in the average diameter of the egg granuloma., Conclusions: Our findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide.

Despite the seriousness of schistosomiasis, its treatment depends only on praziquantel (PZQ), which has begun to lose its efficacy against the emergent Schistosoma mansoni-resistant strains. Therefore, the discovery of a novel schistosomicidal drug is an urgent priority. This study was designed to evaluate treatment with Cucurbita pepo L. (pumpkin) seed oil (PSO) alone and combined with PZQ against S. mansoni in experimentally infected mice. The study involved five groups: GI was the normal control; GII was the infected control; GIII was treated with an oral dose of PZQ of 500 mg/kg/day for two successive days, starting in the sixth week post infection; GIV was treated with an oral dose of PSO of 50 mg/kg/day for four weeks, starting in the fourth week post infection; and GV was treated with combined PSO-PZQ. Worm burden, tissue egg load and oogram pattern were estimated, and the ultrastructure alterations were examined. Histopathological examination of granuloma diameters, collagen deposition (Picro Sirius red stain), and angiogenesis (immunohistochemical expression of CD34+) was conducted and serum liver enzymes were measured to assess the liver condition. Moreover, the oxidative stress was evaluated by determining the amounts of malondialdehyde and superoxide dismutase in liver homogenates. The results revealed significant changes in all the assessed parameters with PSO administration. However, PZQ was significantly more effective as an antiparasitic agent, whereas PSO was better in terms of fibrosis and oxidative stress. The most significant results were obtained in group V, which may be attributed to a synergy between PZQ and PSO, with antiparasitic, antioxidant and antifibrotic properties.

Chronic schistosomiasis and its intestinal manifestations can lead to anaemia. However, schistosomiasis resulting in anaemia is rare in the UK. This report aims to raise awareness of schistosomiasis in immigrants to the UK and prevent missed diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In an effort to overcome the palatability issues currently constraining the effective delivery of praziquantel (PZQ) via feed to treat monogenean parasites in yellowtail kingfish, this study compared the bioavailability and palatability of PZQ in hydrogenated castor oil (HCO) solid lipid nanoparticles (SLN) against pure PZQ in this species. Improving bioavailability would facilitate lower dietary inclusion levels to achieve the same therapeutic dose and therefore reduce the bitterness of feeds containing PZQ. Bioavailability was determined by co-administering feed with either pure PZQ, HCO-SLN or HCO-SLN coated with chitosan via intubation and quantifying the pharmacokinetics response. In contrast to studies with mammals, the results demonstrated that PZQ in HCO-SLN had equal bioavailability to pure PZQ in yellowtail kingfish, including when HCO-SLN were coated with chitosan. We hypothesise that the lack of improvement in bioavailability may be due to the lack of M cells and Peyer's patches in fish and the subsequent inability of fish to take nanoparticles directly into the lymphatic system. Furthermore, palatability of the feeds medicated with PZQ was not improved when the PZQ was incorporated into HCO-SLN, possibly due to the low loading rate of PZQ within the HCO-SLN and the subsequent thick coating of nanoparticles that was required on the surface of the feed pellets. Combined, these data demonstrate that the SLN used in the current study are not capable of delivering the benefits required to enable effective in-feed treatment of PZQ against monogenean parasites in yellowtail kingfish., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Schistosomiasis is infrequently seen in the UK, but remains an important cause of haematuria in endemic areas. It may also be complicated by systemic illness, and can affect multiple organs, including the bladder, liver and lungs. We discuss a case of haematuria associated with lower abdominal discomfort and dry cough/wheeze in a returning traveller diagnosed as pulmonary and urinary schistosomiasis, caused by Schistosomahaematobium This case was particularly notable for the radiological findings seen on CT scan of the chest (figure 2A,B), as well as the characteristic sago nodules discovered within the bladder. It is also unusual to see pulmonary schistosomiasis associated with S. haematobium , an organism more typically characterised by bladder involvement. It is important to consider schistosomiasis and its complications, while rare in the western world, it remains an important differential diagnosis in at-risk groups with considerable morbidity if untreated., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Manifestations of neurocysticercosis (NCC) are primarily due to host inflammatory responses directed at drug-damaged or naturally degenerating metacestodes (cysts) of the tapeworm Taenia solium . Prolonged high-dose corticosteroids are frequently required to control this inflammation in complicated disease, often causing severe side effects. Studies evaluating alternatives to corticosteroids are lacking. Here, we describe the clinical course of NCC in 16 patients prescribed etanercept (ETN), a tumor necrosis factor-alpha inhibitor to control inflammation resulting from anthelmintic treatment. Twelve patients with extraparenchymal NCC were administered ETN with corticosteroids (11/12, 91.7%) and/or methotrexate (9/12, 75.0%). The median age of the subgroup with extraparenchymal NCC was 40 years (range 26-57 years) and 66.7% were male. They were administered ETN for a median period of 311 days (range 31-461 days) and then followed for a median of 3.4 years (range 0.3-6.6 years). Among nine assessable patients, all improved clinically after starting ETN and one deteriorated transiently. Of the remaining three, one was lost to follow-up and two patients have improved but had not completed their assigned course. Four additional persons with recurrent perilesional edema (PE) episodes were given ETN for a median of 400.5 days (range 366-854 days) and followed post-ETN for a median of 1.7 years (range 0.2-2.4 years). All PE patients improved and two successfully tapered corticosteroids. Etanercept administration was associated with clinical improvement, stable disease, absence of recurrence, and lack of serious side effects. Etanercept appears to contribute to the control of inflammation and facilitate corticosteroid taper.

Introduction: Schistosomiasis associated pulmonary arterial hypertension belongs to group 1 of the pulmonary hypertension classification and should be considered in any patient with pulmonary hypertension returning from an endemic area., Case Report: A 17-year-old patient was hospitalized for pulmonary hypertension detected during the initial assessment of viral hepatitis B-related cirrhosis with portal hypertension. The initial assessment established the diagnosis of pulmonary hypertension secondary to viral hepatitis B-cirrhosis. The patient's hepatic and haemodynamic condition deteriorated and he was treated with intravenous epoprostenol. This allowed subsequent performance of a liver transplantation. Epoprostenol could then be discontinued. Unexpectedly, histology of the liver explant revealed florid schistosomiasis in addition to hepatitis B cirrhosis., Conclusion: The diagnosis of pulmonary arterial hypertension associated with schistosomiasis may be difficult. It is necessary to repeat the serological studies and, sometimes, to obtain a rectal biopsy. The treatment of pulmonary arterial hypertension associated with schistosomiasis is based on specific therapies and antiparasitic treatment., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Schistosoma infection is associated with immune modulation that can influence responses to non-schistosome antigens. Vaccine responses may be impaired in S. mansoni-infected individuals. We investigated effects of S. mansoni infection on responses to childhood measles catch-up immunisation and of praziquantel treatment on this outcome in a randomised trial., Methodology: The Immune Modulation and Childhood Immunisation (IMoChI) study was based in Entebbe, Uganda. Children aged 3-5 years (193 S. mansoni-infected and 61 uninfected) were enrolled. Infected children were randomised in a 1:1:1 ratio to receive praziquantel 2 weeks before, at time of, or 1 week after, measles catch-up immunisation. Plasma anti-measles IgG was measured at enrolment, 1 week and 24 weeks after measles immunisation. Primary outcomes were IgG levels and percentage of participants with levels considered protective against measles., Results: Anti-measles IgG levels increased following immunisation, but at 1 week post-immunisation S. mansoni-infected, compared to uninfected, children had lower levels of anti-measles IgG (adjusted geometric mean ratio (aGMR) 0.4 [95% CI 0.2-0.7]) and the percentage with protective antibody levels was also lower (adjusted odds ratio 0.1 [0-0.9]). Among S. mansoni-infected children, anti-measles IgG one week post-immunisation was higher among those treated with praziquantel than among those who were not yet treated (treatment before immunisation, aGMR 2.3 [1.5-4.8]; treatment at immunisation aGMR 1.8 [1.1-3.5]). At 24 weeks post-immunisation, IgG levels did not differ between the trial groups, but tended to be lower among previously-infected children who were still S mansoni stool-positive than among those who became stool-negative., Conclusions and Significance: Our findings suggest that S. mansoni infection among pre-school children is associated with a reduced antibody response to catch-up measles immunisation, and that praziquantel treatment improves the response. S. mansoni infection may contribute to impaired vaccine responses in endemic populations; effective schistosomiasis control may be beneficial for vaccine efficacy. This should be further explored., Trial Registration: ISRCTN87107592., Competing Interests: The authors have declared that no competing interests exist.

The tegument of schistosomes is a source of many potential anti-Schistosoma vaccine molecules. This work aimed to assess the protective effects of the adult Schistosoma mansoni tegument treated (TT) with sub-curative praziquantel (PZQ), whether in vivo (in vivo TT) or in vitro (in vitro TT), in murine schistosomiasis. In vitro TT and in vivo TT showed great similarity, and they differed from untreated tegument antigen (Teg) in terms of quantity and quality of protein bands on SDS-PAGE. Two immunization trials were performed, each with 50 mice, divided randomly into five groups of 10 mice each: (1) uninfected control mice (UC), (2) infected mice given phosphate buffer saline + adjuvant (PBS + adjuvant), (3) infected, Teg vaccinated, (4) infected, in vivo TT vaccinated, and (5) infected, in vitro TT vaccinated. All the immunizations with antigens induced mixed Th1/Th2 immune responses, as indicated by significantly high (P < 0.001) specific IgG2a and IgG1 levels, with Th1 predominating, as shown by a diminished IgG1/IgG2a ratio, as well as a high serum concentration of IFN-γ, an absence of IL-4 and increased IL-10. In vitro TT gave the most pronounced response. With respect to reduction of total worm burden, relative to PBS + adjuvant mice, in vitro TT achieved the highest significant (P < 0.001) results, followed by in vivo TT and Teg (51.8-57.04%, 44.6-50.2% and 35.2-39.3%, respectively). In scanning electron microscopy studies, all the tested antigens caused tegumental changes in adult worms, with the worst occurring with in vitro TT, such as retracted ventral sucker, an effect on the gynaecophoric canal, and changes to tubercles. In conclusion, in vitro TT, which is cheap to prepare, could be a potential vaccine against S. mansoni.

Background: Cerebral sparganosis is the most serious complication of human sparganosis. Currently, there is no standard for the treatment of inoperable patients. Conventional-dose praziquantel therapy is the most reported treatment. However, the therapeutic outcomes are not very effective. High-dose praziquantel therapy is a useful therapeutic choice for many parasitic diseases that is well tolerated by patients, but it has not been sufficiently evaluated for cerebral sparganosis. This study aims to observe the prognoses following high-dose praziquantel therapy in inoperable patients and the roles of MRI and peripheral eosinophil absolute counts during follow-up., Methodology: Baseline and follow-up epidemiological, clinical, radiological and therapeutic data related to 10 inoperable patients with cerebral sparganosis that were treated with repeated courses of high-dose praziquantel therapy, with each course consisting of 25 mg/kg thrice daily for 10 days were assessed, followed by analyses of the prognoses, MRI findings and peripheral eosinophil absolute counts., Principal Findings: Baseline clinical data: the clinical symptoms recorded included seizures, hemiparesis, headache, vomiting and altered mental status. Peripheral blood eosinophilia was found in 3 patients. The baseline radiological findings were as follows. Motile lesions were observed in 10 patients, including aggregated ring-like enhancements, tunnel signs, serpiginous and irregular enhancements. Nine of the 10 patients had varying degrees of white matter degeneration, cortical atrophy and ipsilateral ventricle dilation. The follow-up clinical data were as follows. Clinical symptom relief was found in 8 patients, symptoms were eliminated in 1 patient, and symptoms showed no change from baseline in 1 patient. Peripheral blood eosinophilia was found in 2 patients. The follow-up radiological findings were as follows. Motile lesions that were transformed into stable, chronic lesions were found in 8 patients, and motile lesions that were eliminated completely were found in 2 patients., Conclusions: High-dose praziquantel therapy for cerebral sparganosis is effective. The radiological outcomes of motile lesions are an important indicator during the treatment process, especially during follow-ups after clinical symptoms have improved. Peripheral eosinophil absolute counts cannot be used as an effective prognostic indicator., Competing Interests: The authors have declared that no competing interests exist.

The capsalid monogenean Neobenedenia melleni is known as a lethal pathogen for captured marine teleost ornamental fish, if left untreated. This study reports the occurrence of N. melleni parasitizing four species of ornamental reef fish imported into Brazil and maintained in quarantine: Arabian angelfish (Pomacanthus asfur ), yellowbar angelfish (Pomacanthus maculosus), regal angelfish (Pygoplites diacanthus), and bluecheek butterflyfish (Chaetodon semilarvatus). Ten days after the beginning of quarantine, some fish showed behavioral alterations, such as irritability, and corneal opacity, which were rapidly diagnosed to be caused by monogenean parasites by body surface scraping. The fish from the same batch were treated with two applications of 2 mg L-1 praziquantel each at an interval of four days. Seven days after the first treatment, the mucus surface of the fish was re-examined, which did not reveal the parasites presence being delivered for commercialization.

Praziquantel (PZQ) is recommended by the WHO as the first line in treatment of schistosomiasis. Unfortunately, it exhibits low oral bioavailability which can compromise its efficacy. Nanostructures showed promising potential to overcome this problem. Accordingly, the aim of this study was to investigate the effect of niosomal encapsulation of PZQ on its activity on Schistosoma mansoni in vitro and in vivo. PZQ was encapsulated in niosomal formulation comprising span 60, cholesterol with peceol being included as absorption enhancer. The in vitro work determined the schistosomicidal activity and morphological changes after incubation with drug solution or PZQ-niosomes. The in vivo study utilized infected mice which received PZQ orally as solution or as niosomes. The activity was assessed by monitoring egg and worm count in addition to histopathological and immunohistochemical studies. The in vitro studies revealed that niosomes alone caused a 30% death of adult parasites and caused completely coiled body, destruction, and peeling of tubercles and spines, with flattening and effacement of gynecophoric canal, blebbing with niosomes vesicles attached to it. Niosomes containing PZQ at a concentration of 0.001 μg/ml increased the death from 30 to 50% with the corresponding PZQ solution causing only 10% death. The in vivo study reflected of niosome-PZQ over PZQ solution as indicated from significant reduction of adult worm count, hepatic and intestinal egg depositions, hepatic granuloma size, and numbers, with marked reduction of vascular endothelial growth factor expression. The study introduced niosomes as promising carriers for enhanced activity of PZQ.

The importance of implementing paediatric clinical trials for neglected tropical diseases (NTDs) in compliance with the Good Clinical Practices of the International Conference of Harmonisation (ICH-GCP) and other applicable regulatory and ethics guidelines is increasingly being recognised as an essential pathway to provide safe and effective medicines for millions of untreated children living in sub-Saharan Africa (SSA). This paper describes the learnings and challenges faced by the Pediatric Praziquantel Consortium team during the implementation of an industry-sponsored Phase II clinical study in pre-school-aged children infected with schistosomiasis, conducted in remote rural settings in Côte d'Ivoire. The importance of close interactions with the ethics committee, the regulatory and administrative authorities and the rural communities are highlighted. The difficulties faced included obtaining a valid informed consent from the child's parent or guardian, the collection of blood samples from children during the study while respecting cultural beliefs as well as the weak medical research infrastructure. The paper illustrates how a public-private collaborative partnership can promote capacity-building and high-quality NTD paediatric clinical research in SSA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L-PZQ of ODT rac-PZQ and Cysticide at 40 mg/kg was comparable (L-PZQ area under the concentration-time curve from zero to infinity (AUC 0-∞ ) test/reference ratio (90% confidence interval (CI)): 96% (84-111%)), whereas relative bioavailability of ODT L-PZQ 20 mg/kg was ~40% that of Cysticide 40 mg/kg (test/reference: 40% (35-46%)). AUC 0-∞ and peak plasma concentration (C max ) were highly variable in both studies. For both ODTs, L-PZQ AUC 0-∞ showed greater than dose-proportional increase over the ranges tested and a significant food effect. Safety was comparable among formulations. The lower bioavailability of ODT L-PZQ, as well as the high variability and nondose-proportionality of pharmacokinetic (PK) parameters, highlighted the need for a dedicated pediatric dose-finding study for the selection of the most appropriate formulation and dose (L-PZQ ODT or rac-PZQ ODT)., (© 2018 Merck KGaA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Large scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations is the cornerstone of schistosomiasis control, although persisting high prevalence of infections in some areas and growing concerns of PZQ resistance have revealed the limitations of this strategy. Most studies assessing PZQ efficacy have used relatively insensitive parasitological diagnostics, such as the Kato-Katz (KK) and urine-filtration methods, thereby overestimating cure rates (CRs). This study aims to determine the efficacy of repeated PZQ treatments against Schistosoma mansoni infection in school-aged children in Côte d'Ivoire using the traditional KK technique, as well as more sensitive antigen- and DNA-detection methods., Methods: An open-label, randomised controlled trial will be conducted in school-aged children (5 to 18 years) from the region of Taabo, Côte d'Ivoire, an area endemic for S. mansoni. This 8-week trial includes four two-weekly standard doses of PZQ in the "intense treatment" intervention group and one standard dose of PZQ in the "standard treatment" control group. The efficacy of PZQ will be evaluated in stool samples using the KK technique and real-time PCR as well as in urine using the point-of-care circulating cathodic antigen test and the up-converting phosphor, lateral flow, circulating anodic antigen assay. The primary outcome of the study will be the difference in CR of intense versus standard treatment with PZQ on individuals with a confirmed S. mansoni infection measured by KK. Secondary outcomes include the difference in CR and intensity reduction rate between the intense and standard treatment groups as measured by the other diagnostic tests, as well as the accuracy of the different diagnostic tests, and the safety of PZQ., Discussion: This study will provide data on the efficacy of repeated PZQ treatment on the clearance of S. mansoni as measured by several diagnostic techniques. These findings will inform future mass drug administration policy and shed light on position of novel diagnostic tools to evaluate schistosomiasis control strategies., Trial Registration: The study is registered at EudraCT (2016-003017-10, date of registration: 22 July 2016) and ( NCT02868385 , date of registration: 16 August 2016).

While antigens from Schistosoma schistosomula have been suggested as potential vaccine candidates, the association between antibody responses with schistosomula antigens and infection intensity at reinfection is not well known. Schistosoma mansoni-infected individuals were recruited from a schistosomiasis endemic area in Uganda (n = 372), treated with 40 mg/kg praziquantel (PZQ) and followed up at five weeks and at one year post-treatment. Pre-treatment and five weeks post-treatment immunoglobulin (Ig) E, IgG1 and IgG4 levels against recombinant schistosomula antigens rSmKK7, rSmLy6A, rSmLy6B and rSmTSP7 were measured using ELISA. Factors associated with detectable pre-treatment or post-treatment antibody response against the schistosomula antigens and the association between five-week antibody responses and one year post-treatment reinfection intensity among antibody responders were examined. Being male was associated with higher pre-treatment IgG1 to rSmKK7, rSmLy6a and AWA. Five weeks post-treatment antibody responses against schistosomula antigens were not associated with one year post-treatment reinfection intensity among antibody responders' antibody levels against rSmKK7, rSmLy6B and rSmTSP7 dropped, but increased against rSmLy6A, AWA and SEA at five weeks post-treatment among antibody responders. S. mansoni-infected individuals exhibit detectable antibody responses to schistosomula antigens that are affected by treatment. These findings indicate that schistosomula antigens induce highly varied antibody responses and could have implications for vaccine development., (© 2018 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.)

Schistosomiasis is prevalent in Nigeria, and the foremost pathogen is Schistosoma haematobium, which affects about 29 million people. Single dose of the drug praziquantel is often recommended for treatment but the efficacy has not been documented in certain regions. Therefore, this study was designed to assess the impact of single dose praziquantel treatment on S. haematobium infection among school children in an endemic community of South-Western Nigeria. Urine samples were collected from 434 school children and 10 ml was filtered through Nucleopore filter paper before examination for egg outputs by microscopy. The prevalence was 24.9% at pre-treatment. There was no statistically significant difference for the prevalence of infection between males (14.7%) and females (10.2%), although the mean egg count for the females (9.87) was significantly more (P &lt; 0.05) than the males (6.06). At 6 and 12 months post-treatment there was 74.4% and 86.4% reduction in the mean egg count, respectively. Interestingly, an increased prevalence of infection from 2.1% at 6 months to 7.7% at 12 months post-treatment was observed, nonetheless the mean egg count was reduced to 0.27 at 12th month from 1.98 at 6 months post-treatment. Resurgence in the prevalence rate between 6 and 12 months post-treatment with praziquantel is herein reported and the need for a follow-up treatment in endemic areas for adequate impact on schistosomiasis control is discussed.

Larvae of Schistosoma (schistosomula) are highly susceptible to host immune responses and are attractive prophylactic vaccine targets, although cellular immune responses against schistosomula antigens in endemic human populations are not well characterized. We collected blood and stool from 54 Schistosoma mansoni-infected Ugandans, isolated peripheral blood mononuclear cells and stimulated them for 24 hours with schistosome adult worm and soluble egg antigens (AWA and SEA), along with schistosomula recombinant proteins rSmKK7, Lymphocyte Antigen 6 isoforms (rSmLy6A and rSmLy6B), tetraspanin isoforms (rSmTSP6 and rSmTSP7). Cytokines, chemokines and growth factors were measured in the culture supernatants using a multiplex luminex assay, and infection intensity was determined before and at 1 year after praziquantel (PZQ) treatment using the Kato-Katz method. Cellular responses were grouped and the relationship between groups of correlated cellular responses and infection intensity before and after PZQ treatment was investigated. AWA and SEA induced mainly Th2 responses. In contrast, rSmLy6B, rSmTSP6 and rSmTSP7 induced Th1/pro-inflammatory responses. While recombinant antigens rSmKK7 and rSmLy6A did not induce a Th1/pro-inflammatory response, they had an association with pre-treatment infection intensity after adjusting for age and sex. Testing more schistosomula antigens using this approach could provide immune-epidemiology identifiers necessary for prioritizing next generation schistosomiasis vaccine candidates., (© 2018 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.)

Background: Fluralaner provides efficacy against feline ectoparasites following topical administration. Moxidectin is routinely used to treat gastrointestinal nematode infections and prevent heartworm disease caused by Dirofilaria immitis. Praziquantel is routinely used to treat feline tapeworm infections. The safety of a fluralaner plus moxidectin combination topical solution (Bravecto™ Plus, MSD Animal Health) was assessed when administered concurrently with a commercially available praziquantel topical solution (Droncit™ Spot-on, Bayer Animal Health GmbH). The highest dose rates in clinical use were tested., Results: Concurrent topical administration of a fluralaner plus moxidectin and a praziquantel product did not result in adverse findings. One out of ten cats receiving praziquantel only (control group), and two out of ten cats receiving fluralaner plus moxidectin and praziquantel (treatment group) had dandruff-like flakes in their coat at the application site. Two out of the ten control cats and three cats out of the ten treatment group cats had very small amounts of unidentified material (minute crusts or crumbs) at the application site which was only visible during close inspection., Conclusions: The concurrent treatment of cats with fluralaner plus moxidectin and praziquantel at the maximum dose in clinical use was well tolerated.

Background: A spot-on formulation containing fluralaner (280 mg/ml) plus moxidectin (14 mg/ml) (Bravecto® Plus) was developed for the treatment of nematode infections as well as providing 12 weeks of protection against insect and acarine parasites in cats. The effectiveness and safety of this product against feline gastrointestinal nematodes was assessed in naturally-infested, client-owned cats under field conditions in Albania, Bulgaria, Germany and Hungary., Methods: To be eligible for enrollment in this investigator-blinded study cats had to be at least 10 weeks-old, weigh at least 1.2 kg, be clinically healthy, and have a faecal sample testing positive for nematodes no more than eight days prior to treatment. Cats were stratified into blocks of three in order of presentation at each center and randomly allocated in a 2:1 ratio to be treated topically on Day 0 with fluralaner plus moxidectin (minimum dose rates 40 mg/kg and 2 mg/kg, respectively) or emodepside plus praziquantel (minimum dose rates 3 mg/kg and 12 mg/kg, respectively) (Profender®). Faecal samples were collected from cats prior to treatment and 14 ± 4 days later., Results: There were 182 cats randomized to the fluralaner plus moxidectin group, and 91 to the emodepside plus praziquantel group. Prior to treatment the most commonly identified nematode egg was Toxocara cati, found in 79.1 and 82.4% of cats in the fluralaner plus moxidectin and emodepside plus praziquantel groups, respectively. Eggs of Toxascaris leonina were found in 8.2 and 6.6% of cats; of hookworms in 30.8 and 24.2%; and of Capillaria spp. in 7.1 and 4.3%, respectively. After treatment, faecal samples from 98.3% of fluralaner plus moxidectin treated and 96.6% of emodepside plus praziquantel-treated cats were free of nematode ova. Geometric mean faecal egg count reductions for T. cati, the only eggs found in post-treatment faecal samples, were 99.97% and 99.93%, respectively. Treatment with fluralaner plus moxidectin was non-inferior to emodepside plus praziquantel. Both products were safe and well tolerated by cats treated under field conditions., Conclusions: This field study confirms that, in addition to 12-week extended duration flea and tick control, fluralaner plus moxidectin provides broad spectrum treatment of nematodes in cats.

Objective: To analyze the current drug treatment against clonorchiasis in China, in order to promote the standardization of drug treatment and national deworming for clonorchiasis., Methods: All the 10 provinces were enrolled, which reported clonorchiasis in the work report for important helminthiasis in 2016. Then, 20 counties were selected from these 10 provinces. The data on drug treatment including both mass chemotherapy and individual treatment against clonorchiasis were collected and compared., Results: All the 10 provinces had no guideline for mass chemotherapy, while only 3 had that for individual treatment against clonorchiasis. Out of 20 counties, only 1 implemented mass chemotherapy. Among these 20 counties, 13 applied praziquantel in individual treatment, while other 7 employed albendazole. In the 12 counties with clear protocol for praziquantel, the total dosage for a man of 60 kg ranged from 3.6 to 18.0 g, the days and times for administration ranged from 1 to 6 and from 3 to 18, respectively. In the 4 counties with clear protocol for albendazole, the total dosage for a man of 60 kg ranged from 0.8 to 8.4 g, the days and times for administration ranged from 2 to 7 and from 2 to 14, respectively., Conclusions: Nowadays, the guideline on mass chemotherapy for clonorchiasis is inadequate in China. Although individual treatment is applied in many areas, the protocols vary in drugs, dosage, and days and times for treatment. Thus, the national guideline of mass chemotherapy for clonorchiasis should be established, while the protocols for individual treatment should be standardized.

An 11-year-old boy collapsed during morning assembly at his junior high school. The automated external defibrillator detected ventricular fibrillation and provided shock delivery. He was successfully resuscitated and reverted to sinus rhythm. Electrocardiography showed ST-T elevation in the precordial leads. Echocardiography and angiography demonstrated akinesia of the apex and mid-wall of the left ventricle with preserved contraction of the basal segments, which suggested Takotsubo cardiomyopathy. The patient and his family had often eaten uncooked crab, and his father had a past history of infection with Paragonimiasis westermani. The patient had had a persistent cough and chest pain for several weeks. Chest radiograph showed cystic cavities in the left upper lung. Microbiological examination of the sputum demonstrated an egg of P. westermani and immunological assay showed a raised antibody titre to P. westermani. On the12th day of admission, he developed seizures, and magnetic resonance imaging demonstrated cerebral involvement. After the administration of praziquantel for 3 days, the clinical manifestations improved immediately, and echocardiography normalised within 3 weeks. The patient was discharged on the 32nd day + and follow-up was normal. Takotsubo cardiomyopathy following a potentially fatal arrhythmia is a rare cardiac complication associated with pulmonary and central nervous system infection by P. westermani.

Praziquantel is an antiparasitic drug used for decades. Currently, the praziquantel commercial preparation is a racemic mixture, in which only the levo-enantiomer possesses anthelmintic activity. The knowledge of its properties in the solid state and other chemical-physical properties is necessary for improving its efficacy and applications. Drug solid dispersions were prepared with calcium carbonate at 1:5 drug to excipient weight ratio by solvent evaporation method. Then, the modification of the crystal structure of the racemic polymorph of praziquantel in presence of calcium carbonate has been studied by means of several analytical techniques (DSC, TGA, XRD, SEM, FTIR, Raman spectroscopy and chiral liquid chromatography). This study has been completed with atomistic calculations based on empirical interatomic force fields and quantum mechanics methods applied to the crystal structure of praziquantel and of intermolecular interactions. The results evidenced that calcium carbonate provoked a conformational change in the praziquantel molecule yielding the formation of different polymorphs of praziquantel crystal. These alterations were not observed replacing calcium carbonate with colloidal silica as excipient in the solid dispersion., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The recommended strategy for control of schistosomiasis is preventive chemotherapy with praziquantel (PZQ). Pre-school children (PSC) are excluded from population treatment programs. In high endemic areas, these children are also at risk, and require treatment with PZQ. The Government of Kenya initiated the National School-Based Deworming Programme (NSBDP) where PSC in Early Childhood Development Education (ECDE) Centers are only eligible for treatment with albendazole (ABZ) but not with PZQ., Methodology/principal Findings: 400 PSC were enrolled, from 10 randomly selected ECDE Centers in Kwale County, Kenya where children were treated with crushed PZQ tablets mixed with orange juice, at a single dose of 40 mg/kg. Adverse events were assessed 24 hours post-treatment through questionnaires administered to the parents or guardians. Acceptability was determined by observing if the child spat and/ or vomited all or part of the PZQ dose immediately after treatment. Efficacy was assessed by examining urine samples for Schistosoma haematobium eggs in the 5 weeks post-treatment follow-up. Children testing negative for S. haematobium during the follow-up were considered cured. Egg reduction rate (ERR) was calculated as the decrement in the infection intensity (group's geometric mean egg counts per 10 ml of urine) following treatment expressed as a proportion of the pre-treatment infection intensity. Before treatment, 80 out of the 400 children enrolled in the study tested positive for S. haematobium (20.0% (95% confidence interval (CI) 16.4-24.2%). Of these, 41 had infections of heavy intensity (51.3%) while the rest (48.7%) were of light intensity. Five weeks post-treatment, 10 children who had heavy intensity infection were diagnosed with S. haematobium (prevalence: 2.5% (95% CI 1.5-4.9%). Infection intensities decreased significantly from 45.9 (95% CI: 31.0-68.0) eggs/ 10 ml urine to1.4 (95% CI: 1.1-1.7) eggs/ 10 ml urine during pre-and post-treatment respectively. The ERR was 96.9%. There were no severe adverse events during follow up 24 hours post treatment. Treatment tolerability among the 400 children was high as none of the children spat and/ or vomited as observed in this study., Conclusion/significance: The study revealed that crushed PZQ is safe and effective in the treatment of urogenital schistosomiasis in this age group. It is therefore recommended that PZQ should be administered to the PSC in Kwale County., Competing Interests: The authors have declared that no competing interests exist.

Objectives The pharmacokinetics of praziquantel and pyrantel pamoate has never been reported in cats. The present study was designed to establish the plasma concentration-time profile and to derive pharmacokinetic data for a combined formulation of praziquantel and pyrantel in cats, after a single, oral administration. Methods Twenty-two clinically healthy adult cats were used, each receiving a single oral dose of praziquantel (8.5 mg/kg) and pyrantel (100 mg/kg). Blood samples were collected at regular time points up to 48 h post-dosing. Plasma concentrations of praziquantel and pyrantel were measured using a liquid chromatography-mass spectrometry-high-throughput screening method. Results Clinical examination of all cats did not reveal any side effects after oral administration of these medications. The terminal half-life for praziquantel and pyrantel was 1.07 and 1.36 h, respectively. Praziquantel peak concentration (C max ) was 1140 μg/ml, reached at 1.22 h. The plasma concentrations of pyrantel after oral administration were low with a mean C max of 0.11 μg/ml, reached at a T max of 1.91 h. Pyrantel showed a very limited absorption as pamoate salt, suggesting permanence and efficacy inside the gastrointestinal tract, where the adult stages of most parasitic nematodes reside. Conclusions and relevance Pyrantel showed a very limited absorption as pamoate salt. Praziquantel was rapidly absorbed following oral administration and the concentrations achieved suggest that praziquantel could be an effective and safe medication in cats. Although some resistance problems are arising as a result of their long use, these anthelminthic products can still play a major role in parasitic control, especially in geographical areas where the high cost of newer treatments or necessity of parenteral administration could decrease the number of treated animals.

The resistance of anthelminthic drugs makes helminth control difficult. The aim of our study was to assess the efficacy of single dose albendazole and praziquantel drugs among helminth-infected children. A cross-sectional study was conducted from April to June, 2017. Stool examination was done by the Formol-Ether concentration technique. Students infected with geohelminths and s chistosoma mansoni were treated with a single dose of albendazole and praziquantel, respectively. Post-treatment stool examination was performed after two weeks. The magnitude of parasite infection, percentage of egg count reduction and cure rate following treatment were calculated using descriptive statistics. A total of 409 Sebatamet primary school students were included. The total prevalence of intestinal parasitosis was 58%. The cure rate of albendazole against hookworm was only 76.8%. Praziquantel had a 91.4% cure rate against Schistosoma mansoni. Therefore, periodic evaluation of the efficacy of anthelminthic drugs is required.

Neurocysticercosis is the most common parasitic infection of the nervous system and currently represents a serious public health issue in many regions of Latin America, Asia, and Africa. To date, praziquantel is one of the chosen drugs for the treatment of neurocysticercosis. Its mechanism of action is based on the inhibition of different biochemical pathways within the parasite which contribute to its death. Thus, the aim of this work was to analyze, for the first time, whether the nanoformulations of praziquantel would modify the energetic pathway of Taenia crassiceps cysticerci, after an intracranial inoculation in BALB/c mice. Praziquantel nanosuspensions were formulated with polyvinyl alcohol, poloxamer 188, and poloxamer 407, as stabilizers. These formulations exhibited particle size in a range of 74-285 nm and zeta potential values in a range of - 8.1/- 13.2 depending on the type of stabilizer. Physical stability study at both 4 ± 2 and 25 ± 2 °C indicated that praziquantel (PZQ) nanoparticles were stable in terms of solubility and particle size after 120-day storage. In vivo studies demonstrated that those nanosystems were able to produce significant modifications on the concentrations of oxaloacetate, citrate, pyruvate, alpha-ketoglutarate, malate, succinate, lactate, beta-hydroxybutyrate, fumarate, and propionate involved in the metabolism of Taenia crassiceps cysticerci. Therefore, these nanoformulations may be considered as a promising tool to deliver praziquantel to the brain for the effective management of neurocysticercosis.

Introduction and Aim: The carcinogenesis of tubular and papillary cholangiocarcinoma (CCA) differ. The available epidemiologic studies about risk factors for CCA do not differentiate between the tubular and papillary type. The current study investigated the relationship between the number of repeated use of Praziquantel (PZQ) treatments and each type of CCA., Material and Methods: This was a hospital-based, matched, case-control study of patients admitted to Srinagarind Hospital, Khon Kaen University. The patients were 210 pathologically-confirmed cases of CCA, while the controls were 840 subjects diagnosed with other diseases. The 4 controls were individually matched with each case by sex, age, and date of admission. The cases were classified according to location (intrahepatic vs. extrahepatic) and cell type (papillary vs. tubular). Multivariable conditional logistic regression was used for the analysis., Results: After adjusting for confounders, there were statistically significant associations between intrahepatic and papillary CCA and repeated use of PZQ treatment. The respective odds of developing intrahepatic CCA for those who used PZQ once, twice, or more was 1.54 (95%CI:0.92-2.55 ), 2.28 (95%CI:0.91-5.73), and 4.21 (95%CI:1.61-11.05). The respective odds of developing papillary CCA for those who used PZQ once, twice, or more was 1.45 (95%CI:0.80-2.63), 2.96 (95%CI:1.06-8.24), and 3.24 (95%CI:1.09-9.66). There was no association between number of uses of PZQ treatment and developing extrahepatic or tubular CCA., Conclusion: The current study found an association between papillary and intrahepatic CCA and repeated use of PZQ treatment. We suggest further study on the risk factors for papillary and tubular CCA should be performed separately.

Purpose: Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated., Materials and Methods: The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in Schistosoma mansoni -infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data., Results: PZQ-LNCs exhibited good pharmaceutical attributes in terms of size (46-62 nm), polydispersity index (0.01-0.08), EE% (>95%), and sustained release profiles. Results indicated significant efficacy enhancement by reduction in worm burden, amelioration of liver pathology, and extensive damage to the fluke suckers and tegument. This was partly explained by PK data determined in rats. In addition, oral targeting of the worms was supported by the stability of PZQ-LNCs in simulated GI fluids and scanning electron microscopy (SEM) visualization of nanostructures on the tegument of worms recovered from mesenteric/hepatic veins. Cytotoxicity data indicated tolerability of PZQ-LNCs., Conclusion: Data obtained provide evidence for the ability of oral LNCs to target distal post-absorption sites, leading to enhanced drug efficacy. From a practical standpoint, PZQ-LNCs could be suggested as a potential tolerable single lower dose oral nanomedicine for more effective PZQ mass chemotherapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Malaria burden remains high in the sub-Saharan region where helminths are prevalent and where children are often infected with both types of parasites. Although the effect of helminths on malaria infection is evident, the impact of these co-infections is not clearly elucidated yet and the scarce findings are conflicting. In this study, we investigated the effect of schistosomiasis, considering soil-transmitted helminths (STH), on prevalence and incidence of Plasmodium falciparum infection., Methodology: This longitudinal survey was conducted in school-age children living in two rural communities in the vicinity of Lambaréné, Gabon. Thick blood smear light microscopy, urine filtration and the Kato-Katz technique were performed to detect malaria parasites, S. haematobium eggs and, STH eggs, respectively. P. falciparum carriage was assessed at inclusion, and incidence of malaria and time to the first malaria event were recorded in correlation with Schistosoma carriage status. Stratified multivariate analysis using generalized linear model was used to assess the risk of plasmodium infection considering interaction with STH, and survival analysis to assess time to malaria., Main Findings: The overall prevalence on subject enrolment was 30%, 23% and 9% for S. haematobium, P. falciparum infections and co-infection with both parasites, respectively. Our results showed that schistosomiasis in children tends to increase the risk of plasmodium infection but a combined effect with Trichuris trichiura or hookworm infection clearly increase the risk (aOR = 3.9 [95%CI: 1.7-9.2]). The incidence of malaria over time was 0.51[95%CI: 0.45-0.57] per person-year and was higher in the Schistosoma-infected group compared to the non-infected group (0.61 vs 0.43, p = 0.02), with a significant delay of time-to first-malaria event only in children aged from 6 to 10-years-old infected with Schistosoma haematobium., Conclusions: Our results suggest that STH enhance the risk for P. falciparum infection in schistosomiasis-positive children, and when infected, that schistosomiasis enhances susceptibility to developing malaria in young children but not in older children., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Human schistosomiasis, a debilitating and chronic disease, is among a set of 17 neglected tropical infectious diseases of poverty that is currently posing a threat to the wellbeing of 2 billion people in the world. The SHAWN/WASH and MAM programmes in the study area require epidemiological data to enhance their effectiveness. We therefore embarked on this cross-sectional study with the aim of investigating the prevalence, intensity and risk factors of urogenital schistosomiasis., Methodology/ Principal Findings: Interviewed 484 respondents produced terminal urine samples (between 10.00h - 14.00h) which were analyzed with Medi ─Test Combi 10 and centrifuged at 400 r.p.m for 4 minutes using C2 series Centurion Scientific Centrifuge. Eggs of S. haematobium were identified with their terminal spines using Motic Binocular Microscope. Data were analyzed with Epi Info 7. In this study, the overall prevalence and arithmetic mean intensity of the infection were 8.68% (6.39─ 11.64) and 80.09 (30.92─129.28) eggs per 10ml of urine respectively. Urogenital schistosomiasis was significantly associated with knowledge about the snail host (χ2 = 4.23; P = 0.0398); water contact activities (χ2 = 25.788; P = 0.0001), gender (χ2 = 16.722; P = 0.0001); age (χ2 = 9.589; P = 0.0019); economic status of school attended (χ2 = 4.869; P = 0.0273); residence distance from open water sources (χ2 = 10.546; P = 0.0012); mothers' occupational (χ2 = 6.081; P = 0.0137) and educational status (χ2 = 4.139; P = 0.0419)., Conclusion/ Significance: The overall prevalence obtained in this survey shows that the study area was at a low-risk degree of endemicity for urogenital schistosomiasis. Beneath this is a subtle, latent and deadly morbidity-inducing heavy mean intensity of infection, calling for urgent implementation of WHO recommendation that MAM with PZQ be carried out twice for School-Age Children (enrolled or not enrolled) during their primary schooling age (once each at the point of admission and graduation). The criteria for classifying endemic areas for schistosomiasis should also be reviewed to capture the magnitude of mean intensity of infection rather than prevalence only as this may underplay its epidemiological severity., Competing Interests: The authors have declared that no competing interests exist.

Background: Schistosomiasis and soil-transmitted helminthiasis (STH) are endemic diseases in Burundi. STH control is integrated into health facilities (HF) across the country, but schistosomiasis control is not. The present study aimed to assess the capacity of HF for integrating intestinal schistosomiasis case management into their routine activities. In addition, the current capacity for HF-based STH case management was evaluated., Methods: A random cluster survey was carried out in July 2014, in 65 HF located in Schistosoma mansoni and STH endemic areas. Data were collected by semi-quantitative questionnaires. Staff with different functions at the HF were interviewed (managers, care providers, heads of laboratory and pharmacy and data clerks). Data pertaining to knowledge of intestinal schistosomiasis and STH symptoms, human and material resources and availability and costs of diagnostic tests and treatment were collected., Findings: Less than half of the 65 care providers mentioned one or more major symptoms of intestinal schistosomiasis (abdominal pain 43.1%, bloody diarrhoea 13.9% and bloody stool 7.7%). Few staff members (15.7%) received higher education, and less than 10% were trained in-job on intestinal schistosomiasis case management. Clinical guidelines and laboratory protocols for intestinal schistosomiasis diagnosis and treatment were available in one third of the HF. Diagnosis was performed by direct smear only. Praziquantel was not available in any of the HF. The results for STH were similar, except that major symptoms were more known and cited (abdominal pain 69.2% and diarrhoea 60%). Clinical guidelines were available in 61.5% of HF, and albendazole or mebendazole was available in all HF., Conclusions: The current capacity of HF for intestinal schistosomiasis and STH detection and management is inadequate. Treatment was not available for schistosomiasis. These issues need to be addressed to create an enabling environment for successful integration of intestinal schistosomiasis and STH case management into HF routine activities in Burundi for better control of these diseases.

Background : Schistosomiasis is a major neglected disease for which the current control strategy involves mass treatment with praziquantel, the only available drug. Hence, there is an urgent need to develop new antischistosomal compounds. Methods : The antischistosomal activity of hederacolchiside A1 (HSA) were determined by total or female worm burden reductions in mice harboring Schistosoma japonicum or S. mansoni . Pathology parameters were detected on HSA against 1-day-old S. japonicum -harboring mice. Moreover, we confirmed the antischistosomal effect of HSA on newly transformed schistosomula (NTS) of S. japonicum in vitro. Results : HSA, a natural product isolated from Pulsatilla chinensis (Bunge) Regel, was initially corroborated to possess promising antischistosomal properties. We demonstrated that HSA had high activity against S. japonicum and S. mansoni less in 11 days old parasites harbored in mice. The antischistosomal effect was even more than the currently used drugs, praziquantel, and artesunate. Furthermore, HSA could ameliorate the pathology parameters in mice harboring 1-day-old juvenile S. japonicum . We also confirmed that HSA-mediated antischistosomal activity is partly due to the morphological changes in the tegument system when NTS are exposed to HSA. Conclusions : HSA may have great potential to be an antischistosomal agent for further research.

The aim of the present investigation was to enhance the solubility, dissolution, and oral bioavailability of praziquantel (PZQ), a poorly water-soluble BCS II drug (Biopharmaceutical Classification System), using a solid dispersion (SD) technique involving hydrophilic copolymers. The SD formulations were prepared by a solvent evaporation method with PZQ and PEG 4000 (polyethylene glycol 4000), PEG 6000, or P 188 polymers at various weight ratios or a combination of PEG 4000/P 188. The optimized SD formulation, which had the highest solubility in distilled water, was further characterized by its surface morphology, crystallinity, and dissolution in 0.1 M HCl with 0.2% w/v of sodium dodecyl sulfate (SDS). X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) revealed the amorphous form of PZQ in the SDs. Moreover, at an oral dosage of 5 mg/kg PZQ, the SDs had higher C max values and areas under the curve (AUCs) compared to those of commercial PZQ tablets. Preparation of PZQ-loaded SDs using PEG 4000/P 188 is a promising strategy to improve the oral bioavailability of PZQ.

Hymenolepis nana is a common intestinal tapeworm that affects humans. Drugs are available for the treatment of this infection, including praziquantel (PZQ), nitazoxanide and niclosamide. Although the drug of choice is praziquantel, due to its high cure rates, indicators of the development of PZQ resistance by different parasites have begun to appear over recent decades. Therefore, this study was a trial to find an alternative to PZQ by assessing the activity of the crude aqueous extract of the medicinal herb Artemisia absinthium against H. nana. In vitro, the extract was used against adult worms at concentrations of 1 and 5 mg/ml, in comparison with 1 mg/ml of PZQ. The times of worm paralysis and death were determined. Ultrastructural morphological changes were studied using transmission electron microscopy (TEM). For the in vivo study, infected mice were divided into untreated, PZQ-treated and A. absinthium-treated groups (400 mg/kg and 800 mg/kg). Pre- and post-treatment egg counts per gram of faeces (EPG) were performed; then, the reduction percentages of the EPG and worm burden were calculated. The best results were obtained with praziquantel. Artemisia absinthium induced worm paralysis, death and ultrastructural alterations, such as tegumental damage, lipid accumulation, and destruction of the nephridial canal and the intrauterine eggs, in a dose-dependent manner. Additionally, significant reductions in the EPG and worm burden were recorded in A. absinthium-treated mice. Although the results obtained with A. absinthium were promising and comparable to PZQ, further studies using different extracts, active ingredients and concentrations against different parasites should be conducted.

Background: Urinary schistosomiasis is endemic in many rural communities of Nigeria and school aged children are mostly affected. A cross-sectional study was carried out to assess the prevalence and intensity of urinary schistosomiasis infection among 251 school aged children in two communities of Ovia South West LGA of Edo State, Nigeria, as well as their knowledge on the control/elimination measures., Methods: Urine samples were collected and examined by microscopy using filtration technique. In addition, a questionnaire survey was conducted among school-aged children and health care providers, probing their knowledge, attitude and practices on on-going control activities., Results: The prevalence of urinary schistosomiasis among the school-aged children was 65.3%. The prevalence was generally higher among females (68.8%) and children in the age groups 10-14 (69.9%). The intensity of infection ranged from 1 to 5044 (mean=449.8) eggs/10ml of urine with a higher proportion having heavy infections (76.8%, P<0.05). Water contact was attested by 123 (49.0%) of the children; of these 123, 74 (60.1%) were infected. The children's knowledge on urinary schistosomiasis was deficient., Conclusion: The high prevalences reported in these communities require integrated approach to control which essentially should incorporate the provision of safe water supply and sanitary facilities, and health education in addition to the annual mass praziquantel distribution, to reduce transmission., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)