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Bioorganic & Medicinal Chemistry Jul 2017Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a... (Review)
Review
Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study.
Topics: Animals; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neglected Diseases; Oxamniquine; Praziquantel; Schistosoma mansoni; Structure-Activity Relationship
PubMed: 28495384
DOI: 10.1016/j.bmc.2017.04.031 -
PLoS Pathogens Jul 2023Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is... (Review)
Review
Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is the only recommended drug for human schistosome infection. However, the lack of efficacy of praziquantel against juvenile worms and concerns about the emergence of drug resistance are driving forces behind the research for an alternative medication. Schistosomes are obligatory parasites that survive on nutrients obtained from their host. The ability of nutrient uptake depends on their physiological structure. In short, the formation and maintenance of the structure and nutrient supply are mutually reinforcing and interdependent. In this review, we focus on the structural features of the tegument, esophagus, and intestine of schistosomes and their roles in nutrient acquisition. Moreover, we introduce the significance and modes of glucose, lipids, proteins, and amino acids intake in schistosomes. We linked the schistosome structure and nutrient supply, introduced the currently emerging targets, and analyzed the current bottlenecks in the research and development of drugs and vaccines, in the hope of providing new strategies for the prevention and control of schistosomiasis.
Topics: Animals; Humans; Praziquantel; Schistosomiasis; Schistosoma japonicum; Schistosoma haematobium; Schistosoma mansoni; Eating
PubMed: 37498810
DOI: 10.1371/journal.ppat.1011498 -
Trends in Parasitology Jan 2021Efforts to eliminate schistosomiasis are hindered by incomplete efficacy of the only FDA-approved antischistosomal drug, praziquantel. By using postgenomic technologies,...
Efforts to eliminate schistosomiasis are hindered by incomplete efficacy of the only FDA-approved antischistosomal drug, praziquantel. By using postgenomic technologies, Wendt et al. and Wang et al. deciphered the function of several genes required for worm survival and pathogenesis, which opens the way for the development of innovative parasite-targeted therapies.
Topics: Animals; Praziquantel; RNA-Seq; Schistosoma mansoni; Schistosomiasis; Schistosomicides
PubMed: 33168425
DOI: 10.1016/j.pt.2020.10.010 -
BioMed Research International 2021Soil-transmitted helminths (STHs) and are the main causes of morbidity among schoolchildren in the tropics. A school-based deworming program was launched to control and...
BACKGROUND
Soil-transmitted helminths (STHs) and are the main causes of morbidity among schoolchildren in the tropics. A school-based deworming program was launched to control and eliminate the infection in endemic countries including Ethiopia. Although periodic deworming is conducted in endemic areas, the prevalence of the infection is high in the country. In addition, periodic evaluation of the efficacy of the anthelminthic drug is limited.
OBJECTIVE
This study is aimed at checking the efficacy of mebendazole and praziquantel with the respective STHs and parasites.
METHODS
A longitudinal study was conducted from February to March 2018 among 422 schoolchildren. Stool samples were collected at baseline and at 2 and 4 weeks posttreatment and were processed using the Kato-Katz technique. Schoolchildren positive for STHs were treated with mebendazole and those positive for with praziquantel. After two weeks, a second round of stool was collected and examined, and then, single-dose redosing was given to each positive child. Lastly, the third stool sample was collected two weeks after the initiation of the redosing and checked for STHs and parasites. A close follow-up of students who were treated was done. All the data were entered and analyzed using SPSS version 20 for analysis. Descriptive statistics was used to compute the cure rate and egg reduction rate of mebendazole and praziquantel.
RESULTS
Among 422 participants, the prevalence of STHs, hookworm, , and was 44.7%, 35.1%, 21.1%, and 13.9%, respectively. The cure rate of mebendazole against increased from 60% in the single dose to 100% in redosing after two weeks. The cure rate of mebendazole against hookworm also increased from 32.4% in the single dose to 91.0% in the redosing. The cure rate of praziquantel against -infected children was 91.5% in the first round and 100% in the redosing phase. There was a 98.6-100% egg reduction rate in the redosing regimen of both drugs.
CONCLUSION
The cure and egg reduction rates of single-dose mebendazole in the treatment of hookworm and are lower at week two than at redosing, while cure and egg reduction rates of single-dose praziquantel are satisfactory to treat . Therefore, single-dose praziquantel to and redosing of single-dose mebendazole to and hookworm infections can be used for treatment purposes.
Topics: Adolescent; Animals; Child; Ethiopia; Female; Geography; Helminthiasis; Helminths; Humans; Male; Mebendazole; Ovum; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Schools; Soil; Students; Treatment Outcome
PubMed: 34327236
DOI: 10.1155/2021/6682418 -
International Journal of Pharmaceutics Sep 2023In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely...
In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P2/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M.
Topics: Animals; Mice; Praziquantel; Niclosamide; Antiparasitic Agents; Pharmaceutical Preparations; Spectroscopy, Fourier Transform Infrared; Anthelmintics; Schistosoma mansoni
PubMed: 37579827
DOI: 10.1016/j.ijpharm.2023.123315 -
PLoS Neglected Tropical Diseases 2014Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.
METHODOLOGY/PRINCIPAL FINDINGS
A systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n=17,017) and egg reduction rate (ERR, n=13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2-98.0) for S. japonicum, 77.1% (68.4-85.1) for S. haematobium, 76.7% (95%CI 71.9-81.2) for S. mansoni, and 63.5% (95%CI 48.2-77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4-67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.
CONCLUSIONS/SIGNIFICANCE
The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.
Topics: Africa; Animals; Anthelmintics; Feces; Humans; Incidence; Intestines; Praziquantel; Schistosoma haematobium; Schistosomiasis haematobia; Schistosomiasis mansoni; Treatment Outcome
PubMed: 25412105
DOI: 10.1371/journal.pntd.0003286 -
Experimental Parasitology 2022This study was planned to evaluate the in vitro and in vivo antischistosomal effects of the widely used antihypertensive drugs, nifedipine (NIF) and diltiazem (DTZ), and...
AIM
This study was planned to evaluate the in vitro and in vivo antischistosomal effects of the widely used antihypertensive drugs, nifedipine (NIF) and diltiazem (DTZ), and their combinations with praziquantel (PZQ) on early and late Schistosoma (S.) mansoni infections 21- and 45- days old stages.
METHODS
In the In vitro study, Calcium channel blockers (CCBs), NIF and DTZ were added to schistosomula and adult worm cultures in different concentrations 10, 20 and 30 mg/ml. The mortality percentage was calculated 1, 12 and 24 h after incubation. In vivo, NIF and DTZ either alone or combined with PZQ were used to treat male albino mice. The parasitological and total immunoglobulin (Ig) G and IgM anti-soluble egg antigen (SEA) were assessed to demonstrate the disease severity.
RESULTS
In the In vitro study, 10 mg/ml NIF induced 100% mortality percentage of both schistosomula and adult worms after 24 h incubation, while DTZ induced similar mortality percentage at 30 mg/ml concentration. In vivo results showed that early or late combination of 30 mg/kg of NIF, but not DTZ, significantly (P <0.05) enhanced the reductive efficacy of PZQ based on the parasitological data. The maximal reduction (P <0.05) of anti-SEA IgM and IgG levels was developed during NIF-PZQ administration 21- (1.12 ± 0.06 and 1.09 ± 0.04, respectively) or 45- (1.00 ± 0.03 and 0.8 ± 0.06, respectively) days post infection (PI), compared to either PZQ or NIF individual treatments. The decreased concentration of anti-SEA antibodies was correlated with the diminished granulomatous diameter and disease severity.
CONCLUSION
Nifedipine improved PZQ chemotherapy targeting either early or late S. mansoni infection in mice compared to the PZQ mono-therapy. Administering NIF can be considered as a promising drug candidate for schistosomiasis chemotherapy.
Topics: Animals; Anthelmintics; Diltiazem; Immunoglobulin G; Immunoglobulin M; Male; Mice; Nifedipine; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni
PubMed: 35398100
DOI: 10.1016/j.exppara.2022.108256 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Apr 2022To investigate long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) interactions and identify the critical gene regulatory network during infections and...
OBJECTIVE
To investigate long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) interactions and identify the critical gene regulatory network during infections and praziquantel treatment using whole transcriptome sequencing.
METHODS
A total of 110 male C57BL/6 mice were randomly divided into the control group, the infection group and the treatment group. Mice in the infection treatment and the control group were infected with cercariae via the abdomen, and liver specimens were sampled from 10 mice 3, 6, 8 weeks post-infection. Praziquantel treatment was given to mice in the treatment group 8 weeks post-infection, and liver specimens were sampled from 10 mice 2, 4, 6, 8, 10 weeks post-treatment. Total RNA was isolated from mouse liver specimens, and the transcriptome library was constructed for highthroughput whole transcriptome sequencing. The significant differentially expressed genes were subjected to functional annotations, Gene Ontology (GO) terms enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Correlation analysis of liver specimens was performed using R Corrplot and Himsc functions, and the lncRNAmiRNA-mRNA interaction network analysis was performed using R MixOmics and Himsc functions.
RESULTS
There were 1 176 differentially expressed miRNAs, 5 270 differentially expressed mRNAs, and 2 682 differentially expressed lncRNAs between the infection group and the control group, 1 289 differentially expressed miRNAs, 7 differentially expressed mRNAs, and 69 differentially expressed lncRNAs between the treatment group and the infection group, and 1 210 differentially expressed miRNAs, 4 456 differentially expressed mRNAs, and 2 016 differentially expressed lncRNAs between the treatment group and the control group. Correlation analysis showed a higher correlation of gene expression between the treatment group and the control group. Principal component analysis showed obvious separate clustering between the infection group and the treatment group. The differentially expressed genes with significant relevance were significantly enriched in 24 GO terms, including arachidonic acid metabolic process, xenobiotic catabolic process, unsaturated fatty acid metabolic process, xenobiotic metabolic process, long-chain fatty acid metabolic process, and 8 KEGG metabolic pathways, including cholesterol metabolism, tyrosine metabolism, linoleic acid metabolism, retinol metabolism, and steroid hormone biometabolism.
CONCLUSIONS
There were 23 mRNAs including Cyp2b9 and 14 lncRNAs including Rmrpr in the core position of the gene regulatory network, which may play a critical role in infections and praziquantel treatment, and 9 miRNAs including miR-8105 may serve as potential molecular markers for diagnosis of infections.
Topics: Animals; Female; Gene Expression Profiling; Gene Regulatory Networks; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Praziquantel; RNA, Long Noncoding; RNA, Messenger; Schistosomiasis japonica; Xenobiotics
PubMed: 35537834
DOI: 10.16250/j.32.1374.2021299 -
PLoS Neglected Tropical Diseases Sep 2020Despite the reported success in reducing morbidity, praziquantel alone is insufficient for the control and elimination of schistosomiasis, partly due to its poor... (Comparative Study)
Comparative Study Randomized Controlled Trial
Efficacy and safety of praziquantel and dihydroartemisinin piperaquine combination for treatment and control of intestinal schistosomiasis: A randomized, non-inferiority clinical trial.
BACKGROUND
Despite the reported success in reducing morbidity, praziquantel alone is insufficient for the control and elimination of schistosomiasis, partly due to its poor efficacy against the juvenile worms. Artemisinin derivatives are effective against juvenile worms but are less effective against adult worms. We compared the safety and efficacy of praziquantel and Dihydroartemisinin-piperaquine combination against the standard praziquantel alone for treatment of intestinal schistosomiasis.
METHODS
In this randomized, open-label, non-inferiority trial, 639 Schistosoma mansoni infected children were enrolled and randomized to receive either praziquantel alone or praziquantel plus Dihydroartemisinin-piperaquine combination. Two stool samples were collected on consecutive days at baseline, 3 and 8 weeks post-treatment and analyzed using thick smear Kato Katz method. Efficacy was assessed by cure and egg reduction rates at 3 and 8 weeks post-treatment. Adverse events were assessed within four hours of drugs intake. The primary outcome was cure rates at 8 weeks of post-treatment. Secondary outcomes were egg reduction rates at 8 weeks of post-treatment and treatment-associated adverse events.
RESULTS
At 3 weeks of post-treatment, cure rates were 88.3% (263/298, 95% CI = 84.1%- 91.4%) and 81.2% (277/341, 95% CI = 76.7%- 85.0%) for the combination therapy and praziquantel alone, respectively (p < 0.01, odds ratio (OR) = 1.74, 95% CI of OR = 1.11 to 2.69). At 8 weeks, there was a significant drop in the cure rates in praziquantel alone group to 63.9% (218/341, 95% CI = 58.7%- 68.8%) compared to 81.9% (244/298, 95% CI = 77.1%- 85.8%) in the combination therapy group (p < 0.0001, OR = 2.55, 95%CI of OR = 1.75 to 3.69). Egg reduction rates at 8 weeks post-treatment were significantly higher in the combination therapy group 93.6% (95% CI = 90.8%- 96.4%) compared to 87.9% (95% CI = 84.4%- 91.4%) in the praziquantel only group (p = 0.01). On both Univariate and Multivariate regression analysis, type of treatment received was a significant predictor of cure at week 8 post-treatment. Overall, 30.8% (95% CI = 27.2%- 34.4%) of the study participants experienced mild and transient treatment-associated adverse events, post-treatment abdominal pain (27.1%) being the most common adverse event observed. There was no significant difference in the overall occurrence of adverse events between the two treatment groups.
CONCLUSION
Praziquantel and Dihydroartemisinin piperaquine combination therapy is safe, and more efficacious compared to praziquantel alone for the treatment of intestinal schistosomiasis. Further studies are needed to explore if the combination therapy can be considered as an option for mass drug administration to control and eventually eliminate schistosomiasis.
Topics: Adolescent; Animals; Anthelmintics; Artemisinins; Child; Drug Therapy, Combination; Feces; Female; Humans; Intestines; Male; Praziquantel; Quinolines; Schistosoma mansoni; Schistosomiasis mansoni; Tanzania; Treatment Outcome
PubMed: 32966290
DOI: 10.1371/journal.pntd.0008619 -
International Journal For Parasitology.... Aug 2021Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice... (Review)
Review
Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma, praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes.
Topics: Animals; Drug Discovery; Humans; Oxamniquine; Praziquantel; Schistosoma mansoni; Schistosomiasis
PubMed: 34111649
DOI: 10.1016/j.ijpddr.2021.05.002