-
Journal of Pharmacokinetics and... Jun 2022Racemic praziquantel (PZQ) is the standard treatment for schistosomiasis and liver fluke infections (opisthorchiasis and clonorchiasis). The development of an optimal...
R-praziquantel integrated population pharmacokinetics in preschool- and school-aged African children infected with Schistosoma mansoni and S. haematobium and Lao adults infected with Opisthorchis viverrini.
Racemic praziquantel (PZQ) is the standard treatment for schistosomiasis and liver fluke infections (opisthorchiasis and clonorchiasis). The development of an optimal pediatric formulation and dose selection would benefit from a population pharmacokinetic (popPK) model. A popPK model was developed for R-PZQ, the active enantiomer of PZQ, in 664 subjects, 493 African children (2-15 years) infected with Schistosoma mansoni and S. haematobium, and 171 Lao adults (15-78 years) infected with Opisthorchis viverrini. Racemate tablets were administered as single doses of 20, 40 and 60 mg/kg in children and 30, 40 and 50 mg/kg in 129 adults, and as 3 × 25 mg/kg apart in 42 adults. Samples collected by the dried-blood-spot technique were assayed by LC-MS/MS. A two-compartment disposition model, with allometric scaling and dual first-order and transit absorption, was developed using Phoenix™ software. Inversely parallel functions of age described the apparent oral bioavailability (BA) and clearance maturation in children and ageing in adults. BA decreased slightly in children with dose increase, and by 35% in adults with multiple dosing. Crushing tablets for preschool-aged children increased the first-order absorption rate by 64%. The mean transit absorption time was 70% higher in children. A popPK model for R-PZQ integrated African children over 2 years of age with schistosomiasis and Lao adults with opisthorchiasis, and should be useful to support dose optimization in children. In vitro hepatic and intestinal metabolism data would help refining and validating the model in younger children as well as in target ethnic pediatric and adult groups.
Topics: Adult; Animals; Anthelmintics; Child; Child, Preschool; Chromatography, Liquid; Humans; Laos; Opisthorchiasis; Opisthorchis; Praziquantel; Schistosoma mansoni; Schistosomiasis; Tandem Mass Spectrometry
PubMed: 35024995
DOI: 10.1007/s10928-021-09791-8 -
Trends in Parasitology Feb 2020Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic... (Review)
Review
Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic blood flukes. Treatment of schistosomiasis has relied on a single drug - praziquantel (PZQ) - for decades. The utility of PZQ as an essential medication is, however, intertwined with a stark gap in our knowledge as to how this drug works. No flatworm target has been identified that readily explains how PZQ paralyzes and damages schistosomes. Recently, a schistosome ion channel was discovered that is activated by PZQ and displays characteristics which mirror key features of PZQ action on schistosomes. Here, the journey to discovery of this target, properties of this ion channel, and remaining questions are reviewed.
Topics: Animals; Anthelmintics; Ion Channels; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 31787521
DOI: 10.1016/j.pt.2019.11.002 -
Acta Tropica Feb 2023Schistosomiasis, an ancient and neglected tropical disease, which poses a huge threat to over 200 million people globally. It is necessary to have a general summary of...
BACKGROUND
Schistosomiasis, an ancient and neglected tropical disease, which poses a huge threat to over 200 million people globally. It is necessary to have a general summary of schistosomiasis research after the new roadmap 2021-2030 issued by WHO. This study analyzes the current status of schistosomiasis research from the perspective of the One Health concept by analyzing important research literature published from 2011 to 2020, while further highlighting research priorities, difficulties, and research directions in order to propose suggestions for tropical disease studies research.
METHODS
Published literature related to schistosomiasis was searched from the Web of Science Core Collection (WoSCC) database. Focusing on a visual analysis of the main research literature in the field of schistosomiasis, CiteSpace software was used to conduct co-occurrence analysis with keywords, countries, institutions, and authors. Moreover, clustering and burst analyses of keywords and co-citation analysis of authors, publications, and journals were performed.
RESULTS
A total of 6638 schistosomiasis-related articles were published from 2011 to 2020, all of which can be sourced from the WoSCC database. The publication of schistosomiasis research has remained stable over the past 10 years, and contains studies in the area of human epidemiology, animal surveillance and the environment. The top five high-frequency keywords included Schistosoma mansoni, schistosomiasis, infection, praziquantel, and Schistosoma japonicum. The keywords formed nine clusters, including praziquantel, epidemiology, Schistosoma japonicum, helminths, protein, diagnosis, schistosomiasis, response, and haematobium. In recent years, most research studies focused on the mechanism of liver fibrosis, eliminating schistosomiasis, controlling risk factors, and the relationship between schistosomiasis infection and host immunity. The most productive countries include the United States, China, and Brazil, and the most productive institutions are the University of Basel, the Swiss Tropical and Public Health Institute, and the University of São Paulo. Highly productive authors include Jürg Utzinger and Donald P. McManus. At the time of writing, the author with the highest co-citation frequency (993 times) was Peter Hotez, and the journal with the highest co-citation frequency (3,720 times) was PLoS Neglected Tropical Diseases. Human schistosomiasis, published by Colley et al. (2014), was the most frequently co-cited publication (494 times).
CONCLUSIONS
This study provides a preliminary description of the current status of schistosomiasis research and an initial exploration of future research directions. The One Health concept was applied in the field of schistosomiasis control, as confirmed by this bibliometric analysis. Our study provides guidance for the development of research on schistosomiasis and other neglected tropical diseases.
Topics: Animals; Humans; United States; Praziquantel; Retrospective Studies; Schistosomiasis; Bibliometrics; Schistosoma japonicum; Neglected Diseases
PubMed: 36372254
DOI: 10.1016/j.actatropica.2022.106750 -
European Journal of Clinical... Aug 2019The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites,... (Randomized Controlled Trial)
Randomized Controlled Trial
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 (α = 0.05). The geometric mean ratios of the AUC and C were found to be 176.8% and 227% respectively. The 90% CI of the AUC and C 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.
Topics: Adult; Anthelmintics; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Feasibility Studies; Healthy Volunteers; Humans; Ketoconazole; Male; Praziquantel; Young Adult
PubMed: 31089768
DOI: 10.1007/s00228-019-02663-8 -
PLoS Pathogens Jul 2023Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for...
Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
Topics: Animals; Humans; Praziquantel; Oxamniquine; Schistosomiasis; Schistosoma mansoni; Combined Modality Therapy; Neglected Diseases; Schistosomiasis mansoni; Anthelmintics
PubMed: 37428793
DOI: 10.1371/journal.ppat.1011018 -
Future Medicinal Chemistry 2015
Topics: Animals; Anthelmintics; Drug Resistance; Humans; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 25996058
DOI: 10.4155/fmc.15.16 -
Parasites & Vectors Sep 2020The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of...
BACKGROUND
The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy.
METHODS
Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey's post-hoc test for pairwise comparisons.
RESULTS
Lipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures.
CONCLUSIONS
The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.
Topics: Administration, Oral; Animals; Disease Models, Animal; Drug Combinations; Drug Compounding; Female; Humans; Male; Mice; Nanocapsules; Phosphorylcholine; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides
PubMed: 32933556
DOI: 10.1186/s13071-020-04346-1 -
Acta Tropica Feb 2023Schistosomes infect over 200 million people worldwide, but few studies have characterized the effects of Schistosoma mansoni infection and effective treatment on the...
Schistosomes infect over 200 million people worldwide, but few studies have characterized the effects of Schistosoma mansoni infection and effective treatment on the lower gastrointestinal mucosa. In this prospective cohort study, we compared the clinical findings on sigmoidoscopy and laboratory measures in Tanzanian adults with and without S. mansoni infection at baseline and 6 months after praziquantel treatment. Grading of the endoscopic findings was done using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. Schistosome infection was confirmed by stool microscopy and serum circulating anodic antigen (CAA). Baseline comparisons were performed in Stata using Fisher's exact and Wilcoxon rank-sum tests, and pre- and post-treatment comparisons using Wilcoxon matched-pairs signed-rank and McNemar's tests. We investigated the clinical characteristics of 48 individuals: 32 with and 16 without S. mansoni infection. Infected individuals had greater severity of sigmoid and rectal mucosal abnormalities and higher Mayo scores and serum eosinophils (all p < 0.05) than uninfected individuals at initial evaluation. At 6 months, 28 individuals completed repeat blood tests and sigmoidoscopy. Of these, 14 cleared their baseline infection (n = 7) or experienced a greater than 7-fold decrease in serum CAA (n = 7). Follow-up sigmoidoscopies revealed some improvements in sigmoid and rectal mucosal findings, although Mayo scores were not significantly lower. Both the median erythrocyte sedimentation rates (32.5→12.5 mm/hr) and percent of eosinophils (7.1→3.1%) decreased in this group from baseline to follow-up. S. mansoni infection was associated with mild-to-moderate lower gastrointestinal mucosal abnormalities that were grossly visible during sigmoidoscopy, and these improved partially 6 months after effective treatment with praziquantel. Additional studies, of longer duration and focused on both clinical and mucosal immunologic effects of S. mansoni, could provide additional insight.
Topics: Adult; Animals; Humans; Praziquantel; Schistosoma mansoni; Tanzania; Anthelmintics; Cohort Studies; Prospective Studies; Schistosomiasis mansoni; Mucous Membrane
PubMed: 36410422
DOI: 10.1016/j.actatropica.2022.106752 -
Journal of Biomolecular Structure &... May 2022Schistosomiasis is an infectious tropical disease caused by parasitic flatworm of the genus Schistosoma. This debilitating disease chronically infects about 200 million...
Schistosomiasis is an infectious tropical disease caused by parasitic flatworm of the genus Schistosoma. This debilitating disease chronically infects about 200 million people globally and management relies on chemotherapy. Unfortunately, the solely available schistosomicide (praziquantel) against all forms of adult schistosmes has been faced with numerous drawbacks. Thus, there is an urgent need to design and develop a new regimen for schistosomiasis. In light of this, the current study focuses on inhibiting the schistosome glucose transporter 4 (SGTP4) as a therapeutic candidate for schistosomiasis. Several studies have revealed that Schistosoma parasites require an adequate amount of energy/glucose to survive. We modelled the 3D structure and subsequently used the homology model for docking with praziquantel (PZQ), Licochalcone A, Licarin and Harmonine. The docked complexes were subjected to molecular dynamics using Desmond system of Schrodinger software. Furthermore, the pharmacokinetic parameters of the ligands were investigated using the QikProp tool in the Schrodinger-2019-4 software suite. After performing all the computational analysis, our findings reveal that all four ligands were able to inhibit SGTP4 effectively through the higher glide G score (dock score) of -5.8 (-5.8), -6.5 (-6.4), -7.3 (-7.3) and -4.9 (-4.9) in kcal/mol for praziquantel, licochalcone A, licarin and harmonine respectively against the protein. The molecular simulation further confirmed that the stability of the complexes formed between the ligands and protein is excellent. More so, all the ligands fulfilled oral drugability of both the Lipinski's rule of five and Veber's rules.The findings in this present study provide new useful insights for the design of drugs which can serve as an alternative to praziquantel in the treatment of schistosomiasis through the inhibition of SGTP4.Communicated by Freddie R. Salsbury.
Topics: Animals; Anthelmintics; Humans; Ligands; Praziquantel; Schistosoma; Schistosomiasis
PubMed: 33225839
DOI: 10.1080/07391102.2020.1850363 -
ACS Infectious Diseases May 2021Schistosomiasis, a neglected tropical disease provoked by infection with parasitic blood flukes of the genus , affects almost 240 million people worldwide, and more than...
Schistosomiasis, a neglected tropical disease provoked by infection with parasitic blood flukes of the genus , affects almost 240 million people worldwide, and more than 700 million people live in endemic areas. However, 40 years after the approval of praziquantel as an anthelmintic drug, the pipeline is nearly empty, and no other therapeutic alternative has reached the market. In its roadmap to "eliminate Schistosomiasis as a public health problem by 2030", the World Health Organization calls for the development of new therapeutic interventions. A viewpoint on the learnings from praziquantel research as well as shaping the next generation of drugs is shared.
Topics: Anthelmintics; Humans; Neglected Diseases; Praziquantel; Schistosomiasis
PubMed: 32819092
DOI: 10.1021/acsinfecdis.0c00542