Current drug strategies for the treatment and control of schistosomiasis.

INTRODUCTION: Schistosomiasis, one of the current Neglected Tropical Diseases (NTDs) affects over 230 million people globally, with nearly 700 million at risk in more than 74 countries. Praziquantel (PZQ) has served as the primary treatment for the past four decades; however, its effectiveness is limited as it solely eliminates adult worms. In regions where infections are frequent, PZQ exhibits only temporary efficacy and has restricted potential to disrupt the prolonged transmission of the disease. AREAS COVERED: A comprehensive exploration using the PubMed database was conducted to review current pharmacotherapy approaches for schistosomiasis. This review also encompasses recent research findings related to potential novel therapeutics and the repurposing of existing drugs. EXPERT OPINION: Current schistosoma treatment strategies, primarily relying on PZQ, face challenges like temporary effectiveness and limited impact on disease transmission. Drug repurposing, due to economic constraints, is decisive for NTDs. Despite PZQ's efficacy, its failure to prevent reinfection highlights the need for complementary strategies, especially in regions with persistent environmental foci. Integrating therapies against diverse schistosome stages boosts efficacy and impedes resistance. Uncovering novel agents is essential to address resistance concerns in tackling this neglected tropical disease. Integrated strategies present a comprehensive approach to navigate the complex challenges.

Genome-wide transcriptome analysis of Echinococcus multilocularis larvae and germinative cell cultures reveals genes involved in parasite stem cell function.

The lethal zoonosis alveolar echinococcosis is caused by tumour-like growth of the metacestode stage of the tapeworm Echinococcus multilocularis within host organs. We previously demonstrated that metacestode proliferation is exclusively driven by somatic stem cells (germinative cells), which are the only mitotically active parasite cells that give rise to all differentiated cell types. The Echinococcus gene repertoire required for germinative cell maintenance and differentiation has not been characterised so far. We herein carried out Illumina sequencing on cDNA from Echinococcus metacestode vesicles, from metacestode tissue depleted of germinative cells, and from Echinococcus primary cell cultures. We identified a set of ~1,180 genes associated with germinative cells, which contained numerous known stem cell markers alongside genes involved in replication, cell cycle regulation, mitosis, meiosis, epigenetic modification, and nucleotide metabolism. Interestingly, we also identified 44 stem cell associated transcription factors that are likely involved in regulating germinative cell differentiation and/or pluripotency. By in situ hybridization and pulse-chase experiments, we also found a new general Echinococcus stem cell marker, EmCIP2Ah, and we provide evidence implying the presence of a slow cycling stem cell sub-population expressing the extracellular matrix factor Emkal1. RNA-Seq analyses on primary cell cultures revealed that metacestode-derived Echinococcus stem cells display an expanded differentiation capability and do not only form differentiated cell types of the metacestode, but also cells expressing genes specific for protoscoleces, adult worms, and oncospheres, including an ortholog of the schistosome praziquantel target, EmTRPMPZQ. Finally, we show that primary cell cultures contain a cell population expressing an ortholog of the tumour necrosis factor α receptor family and that mammalian TNFα accelerates the development of metacestode vesicles from germinative cells. Taken together, our analyses provide a robust and comprehensive characterization of the Echinococcus germinative cell transcriptome, demonstrate expanded differentiation capability of metacestode derived stem cells, and underscore the potential of primary germinative cell cultures to investigate developmental processes of the parasite. These data are relevant for studies into the role of Echinococcus stem cells in parasite development and will facilitate the design of anti-parasitic drugs that specifically act on the parasite germinative cell compartment.

Expression profile analysis of the transient receptor potential (TRPM) channel, a possible target of praziquantel in Schistosoma japonicum.

The WHO considers schistosomiasis, which is controlled by the mass administration of the drug praziquantel (PZQ), to be a neglected tropical disease. Despite its clinical use for over four decades, PZQ remains the only choice of chemotherapy against this disease. Regarding the previous studies that demonstrated that PZQ activates the transient receptor potential (TRP) channel in Schistosoma mansoni (Sm.TRPMPZQ), the expression profile of the ortholog of this channel gene (Smp_246790.5) in S. japonicum (EWB00_008853) (Sj.TRPMPZQ) was analyzed. The relative expression of this gene in various stages of the parasite lifecycle was analyzed by quantitative real-time reverse transcription-PCR (qRT-PCR), and the expression of Sj.TRPMPZQ was observed by immunohistochemical staining using anti-serum against the recombinant Sj.TRPMPZQ protein. qRT-PCR revealed the significantly lower mRNA expression in the snail stage in comparison to other stages (p < 0.01). The relative quantity of the Sj.TRPMPZQ expression for paired females, unpaired males, and eggs was 60%, 56%, and 68%, respectively, in comparison to paired males that showed the highest expression (p < 0.05). Interestingly, immunostaining demonstrated that Sj.TRPMPZQ is expressed in the parenchyma which contains muscle cells, neuronal cells and tegument cells in adult worms. This may support the two major effects of PZQ-worm paralysis and tegument disruption-induced by channel activation. Moreover, the channel was expressed in both the eggshell and the miracidia inside, but could not be observed in sporocyst. These results suggest that the expression of Sj.TRPMPQZ corresponds to the known sensitivity of S. japonicum to PZQ.

The potential curative and hepatoprotective effects of platelet rich plasma on liver fibrosis in Schistosoma mansoni experimentally infected mice.

Trapped Schistosoma mansoni eggs trigger fibrotic liver disease that can continue to liver cirrhosis and failure. This work evaluates the outcome of platelet rich plasma (PRP) on S. mansoni-induced liver fibrosis by intraperitoneal (IP) and intrahepatic (IH) routes with/without Praziquantel (PZQ) treatment. Swiss albino mice (n = 162) were divided into non-infected (n = 66) and infected (n = 96) groups, then subdivided into non-treated and treated subgroups with PRP(IP), PRP(IH) 6th and 10th weeks post-infection, PZQ, PZQ + PRP(IP) and PZQ + PRP(IH) 6th and 10th weeks post-infection. Effects of treatments were evaluated by parasitological, histopathological and Immunohistochemical assessments. In the early assessment (12th week post-infection) of infected-treated groups, the mean granuloma number showed significant reduction in groups treated with PZQ + PRP (IH) 10th week, PRP (IP), PZQ + PRP (IP) and PZQ + PRP (IH) 6th week (33.33%, 33%, 27.77% and 27.22%, respectively). Furthermore, the mean granuloma diameter showed significant reduction in groups treated with PRP (IH) 10th week and PZQ + PRP (IP) (24.17% and 15.5%, respectively). Also, the fibrotic index showed significant reduction in groups treated with PZQ + PRP (IP), PRP (IP) and PZQ + PRP (IH) 6th week (48.18%, 46.81% and 41.36%, respectively). Transforming growth factor ß1(TGF-ß1) expression was in correlation with parasitological and histopathological results. Diminished TGF-ß1 expression was mostly in infected groups treated with PZQ + PRP (IP), PZQ + PRP (IH) 6th week and PRP (IP) (88.63%, 88.63% and 77.27%, respectively). In the late assessment (14th week post-infection) of infected treated groups, TGF-ß1expression was reduced in groups treated with PZQ, PRP (IH) 10th weeks, PRP (IP) (83.33%, 66.66%, 33.33% respectively). PRP showed promising anti-fibrotic effects on S. mansoni-induced liver fibrosis.

Praziquantel - 50 Years of Research.

Investigations on praziquantel (PZQ) started fifty years ago by a cooperation between Bayer AG and Merck KGaA. Until today PZQ is the drug of choice for schistosomiasis in human medicine and used in many combinations with antinematode drugs in veterinary medicine. The Sm.TRPMPZQ , a Ca2+ -permeable transient receptor potential (TRP) channel, has been discovered as primary target of PZQ during the last decade. Furthermore, there is a short overview of routes of large-scale synthesis of racemic and pure (R)-PZQ. Until now racemic PZQ is used in veterinary and human medicine. In 2012 the Pediatric Praziquantel Consortium started PZQ chemistry and process development of pure (R)-PZQ for human application. It is hoped that (R)-PZQ will become available for pediatric use soon. The knowledge of the binding pocket of PZQ in Sm.TRPMPZQ allows to design synthesis of PZQ-derivatives of the next generation for a target-site directed screening. A similar screening should also be started for Fasciola hepatica TRPMPZQ .

Extrusion 3D printing of minicaplets for evaluating in vitro & in vivo praziquantel delivery capability.

This study aimed to explore extrusion three dimensional (3D) printing technology to develop praziquantel (PZQ)-loaded minicaplets and evaluate their in vitro and in vivo delivery capabilities. PZQ-loaded minicaplets were 3D printed using a fused deposition modelling (FDM) principle-based extrusion 3D printer and were further characterized by different in vitro physicochemical and sophisticated analytical techniques. In addition, the % PZQ entrapment and in vitro PZQ release performance were evaluated using chromatographic techniques. It was in vitro observed that PZQ was fully released in the gastric pH medium within the period of gastric emptying, that is, 120 min, from the PZQ-loaded 3D printed minicaplets. Furthermore, in vivo pharmacokinetic (PK) profiles of PZQ-loaded 3D printed minicaplets were systematically evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The PK profile of the PZQ-loaded 3D printed minicaplets was established using different parameters such as Cmax, Tmax, AUC0-t, AUC0-∞, and oral relative bioavailability (RBA). The Cmax value of pristine PZQ was found at 64.79 ± 13.99 ng/ml, while PZQ-loaded 3D printed minicaplets showed a Cmax of 263.16 ± 47.85 ng/ml. Finally, the PZQ-loaded 3D printed minicaplets showed 9.0-fold improved oral RBA compared with that of pristine PZQ (1.0-fold). Together, these observations potentiate the desired in vitro and improved in vivo delivery capabilities of PZQ from the PZQ-loaded 3D printed minicaplets.

Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.

Protective role of Balanities aegyptiaca fruit aqueous extract in mice infected with Schistosoma mansoni.

The target of this research was to investigate the effect of Balanities aegyptiaca fruit aqueous extract (200 mg/kg BW), alone or in combination with Praziquantel PZQ (300 mg/kg BW) on some biochemical, parasitological, liver histopathology and immunohistochemical parameters in mice infected with Schistosoma mansoni. Results showed that treatment of S. mansoni-infected mice with B. aegyptiaca alone or in combination with PZQ significantly reduced the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as compared to that of the S. mansoni-infected mice group. Treatment of S. mansoni-infected mice with B. aegyptiaca or PZQ and their combination led to a significant reduction in the activity of malondialdehyde (MDA) as compared with the infected control group. While a significant elevation was observed in the activities of antioxidant enzymes glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and nitric oxide (NO) compared with the infected. Results revealed that the diameter and number of egg granuloma were significantly condensed after treatment of S. mansoni-infected mice with B. aegyptiaca, PZQ or their combination in hepatic and intestinal tissue. The histopathological alterations observed in the liver of S. mansoni-infected mice were remarkably recovered after B. aegyptiaca treatments. The reduction in angiogenesis was mostly observed in the group receiving the combination of B. aegyptiaca and PZQ. The alterations in vascular endothelial growth factor (VEGF) expression were significantly less in the liver sinusoids. Overall, B. aegyptiaca significantly inhibited the liver and intestinal damage accompanied by schistosomiasis. It demonstrated potent antioxidant and immunoprotective activities. This study advises that B. aegyptiaca can be considered promising for the development of a complementary and/or alternative against schistosomiasis.

Pharmacogenetics of Praziquantel Metabolism: Evaluating the Cytochrome P450 Genes of Zimbabwean Patients During a Schistosomiasis Treatment.

Schistosomiasis is a parasitic disease infecting over 236 million people annually, with the majority affected residing on the African continent. Control of this disease is reliant on the drug praziquantel (PZQ), with treatment success dependent on an individual reaching PZQ concentrations lethal to schistosomes. Despite the complete reliance on PZQ to treat schistosomiasis in Africa, the characterization of the pharmacogenetics associated with PZQ metabolism in African populations has been sparse. We aimed to characterize genetic variation in the drug-metabolising cytochrome P450 enzymes (CYPs) and determine the association between each variant and the efficacy of PZQ treatment in Zimbabwean patients exposed to Schistosoma haematobium infection. Genomic DNA from blood samples of 114 case-control Zimbabweans infected with schistosomes were sequenced using the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genes as targets. Bioinformatic tools were used to identify and predict functional effects of detected single nucleotide polymorphisms (SNPs). A random forest (RF) model was then used to assess SNPs most predictive of PZQ efficacy, with a misclassification rate of 29%. SNPs were detected across all six genes, with 70 SNPs identified and multiple functional changes to the CYP enzymes predicted. Only four SNPs were significantly associated with PZQ efficacy using χ2 tests, with rs951840747 (OR: 3.61, p = 0.01) in the CYP1A2 gene having the highest odds of an individual possessing this SNP clearing infection, and rs6976017 (OR: 2.19, p = 0.045) of CYP3A5 determined to be the most predictive of PZQ efficacy via the RF. Only the rs28371702 (CC) genotype (OR: 2.36, p = 0.024) of CYP2D6 was significantly associated with an unsuccessful PZQ treatment. This study adds to the genomic characterization of the diverse populations in Africa and identifies variants relevant to other pharmacogenetic studies crucial for the development and usage of drugs in these populations.

The Effect of Different Formulations of Praziquantel in Reducing Worms in the Prepatent Period of Schistosomiasis in Murine Models.

Schistosomiasis is a widely distributed parasitic disease and one of the most important neglected tropical diseases globally, for which Praziquantel® (PZQ) is the only available treatment. In this context, tests with new PZQ formulations become relevant for disease control. This study evaluated the effects of PZQ treatment in the prepatent phase of schistosomiasis using two formulations: nanoencapsulated (PZQ-NANO) and active pharmaceutical ingredient (PZQ-API). Five experimental groups were established, for which the following serological parameters were evaluated: ALT, AST, ALP, and TP. Animals treated with PZQ-API at 15 and 30 days post-infection showed decreased eggs per gram of feces (EPG) compared to untreated infected animals. The same animals showed reductions of 63.6 and 65.1%, respectively, at 60 days post-infection. Animals treated with PZQ-NANO experienced no significant changes in EPG at any time of observation. Animals treated with either PZQ-API or PZQ-NANO had higher ALT and AST levels in the patent period (60 and 90 days post-infection). Treatment with PZQ, either API or NANO, at 15 days post-infection reduced AST, ALT, and TP levels. It is concluded that prepatent treatment with PZQ-API can reduce the parasite load of infected animals and that treatment at 15 days post-infection can prevent increased serum levels of ALT, AST, and TP.

In vitro and in vivo impacts of nifedipine and diltiazem on praziquantel chemotherapy in murine Schistosoma mansoni.

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.

Antischistosomal effects of Ficus carica leaves extract and/or PZQ on Schistosoma mansoni infected mice.

Currently, praziquantel (PZQ) is the only drug of choice used for treatment of human schistosomes because of its safety and broad-spectrum activity. It is reported that the repeated chemotherapy is complicated by the occurrence of drug resistance to schistosomiasis. So there is an urgent need to develop new drug combinations therapy. The current study aimed to evaluate antischistosomal activity of F. carica leaves extract alone or in combination with PZQ on Schistosoma mansoni infected mice. Mice were experimentally infected with Schistosoma mansoni and orally administrated 6 weeks' post-infection with Fig leaves extract and/or PZQ. Schistosoma mansoni (S. mansoni)-infected mice were separated into four groups: untreated (I), treated with PZQ in dose of 200 mg/kg bw (II), treated with Fig leaves extract dose of 400 mg/kg bw (III). Group IV was treated with dose of Fig leaves extract-PZQ as in groups II and III, respectively. The effect was detected parasitologically using ova count technique and oogram pattern in intestine and liver. The greatest antischistosomal effect was achieved using orally administered Fig leaves extract-PZQ as indicated by total worm burden, tissue egg count and oogram pattern. Fig leaves extract + PZQ induced the therapeutic efficacy over the PZQ dose alone in intestine and liver as shown by a complete absence of immature worms, a very high reduction in the total numbers of tissue egg load (59.81% vs. 61.43% & 67.96% vs. 73.46%), mature eggs (37.86 ± 1.4 vs. 34.14 ± 1.9) and increasing in the total number of dead eggs (62.14 ± 1.4vs.67.29 ± 1.76). The results suggested the curcumin in combination with PZQ as a strong schistosomicidal regimen against S. mansoni. In addition, F. carica leaves extract is a promising for PZQ potentiating its antischistosomal action in animal model infected with S. mansoni. Therefore, the present work conclude that combined treatment has a synergetic effect and could be more promising in the management of schistosomiasis.

Schistosomiasis mansoni: A new therapeutic target for ubiquinol, a natural inhibitor of neutral magnesium-dependent sphingomyelinase in murine model.

Constituting the host-parasite interface and playing a censorious role in host immune response modulation and parasite survival, tegument represents a crucial target for many antischistosomal drugs. Sphingomyelin forms a stable outer leaflet of tegumental membrane-lipid bilayer. Neutral magnesium -dependent sphingomyelinase (Mg2+-nSMase) is a key enzyme in sphingomyelin breakdown was identified in schistosomes. We investigated the in vivo efficacy of ubiquinol, a natural inhibitor of Mg2+-nSMase, in free and niosomes-encapsulated forms, through five-day and 15-day regimens on the early and late Schistosoma mansoni parasitic stages, respectively, compared to PZQ. Oral administration of 300 mg/kg/day ubiquinol-encapsulated niosomes (U-N) showed significant deterioration of the parasitic growth and development in the term of reduction of lung schistosomula burden (39.12%), adult worm burden (50.81%), hepatic and intestinal tissue-egg counts (80.89% and 75.54%, respectively). PZQ and free ubiquinol regimens reported reductions in lung schistosomula counts (45.36% and 22.90%, respectively) and total worm burdens of 86.28% and 24.58%, respectively. U-N therapy revealed worms de-pairing and remarkable diminution in female worms' perimeters and fecundity. Scanning electron microscope revealed disruption of tegumental ridges with excessive longitudinal corrugation. Transmission electron microscope showed testicular and ovarian parenchymal degeneration, signs of immaturity and cell apoptosis. Indirect immunofluorescence assay approved parasite's tegumental changes. Remarkable reduction of granulomas size with amelioration of hepatic pathology and fibrosis were assumed to be attributed to the anti-inflammatory and anti-oxidant properties of ubiquinol. These findings with the drug safety profile suggest that U-N could be a promising candidate for a new antischistosomal drug development.

Influence of schistosomiasis on host vaccine responses.

Schistosomiasis is a debilitating helminthiasis which commonly establishes as a chronic infection in people from endemic areas. As a potent modulator of the host immune response, the Schistosoma parasite and its associated products can directly interfere with its host's ability to mount adequate immune responses to unrelated antigens. As a result, increased attention is gathering on studies assessing the influence of helminths, particularly the causal agent of schistosomiasis, on host responsiveness to vaccines. However, to date, no consensus has been drawn regarding the influence of schistosomiasis on host vaccine responses. Here, we review available evidence on the influence of transgenerational and direct Schistosoma parasite exposure on host immune responses to unrelated vaccines. In addition, we evaluate the potential of praziquantel (PZQ) treatment in restoring schistosomiasis-impacted vaccine responses.

Theoretical and experimental validation of praziquantel with different polymers for selection of an appropriate matrix for hot-melt extrusion.

The selection of an appropriate matrix for the preparation of amorphous extrudate in hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Therefore, it is necessary to have an appropriate knowledge of drug-polymer miscibility, the interaction between the drug-polymer on mixing, and Gibb's free thermal energy of mixing to screen polymers through thermodynamic phase diagrams, to be suitable amorphous matrix system for HME. Here, we evaluated the possibility of three different polymers, namely, Eudragit®EPO, polyvinyl alcohol (PVA), Kollicoat®IR (KIR) with Praziquantel (PZQ), with proper validation of the Flory-Huggins theory and construction of the phase diagram using the melting point depression approach to determine a suitable matrix for HME. The solubility parameter theoretical calculation approach was used as a preliminary study to validate the miscibility of PZQ with three different polymers. Theoretical and experimental validation studies using the Flory-Huggins interaction parameter value using the melting point depression approach and the effect of PZQ loading on the interaction parameter were systematically validated to predict thermodynamic phase diagrams and Gibbs free energy of mixing for screening these polymers for the preparation of amorphous extrudate. Using the phase diagram, the thermal processing temperature for the HME was determined using a T-φ phase diagram to obtain an appropriate matrix. The obtained extrudates were further validated through physical appearance, microscopic structure, thermal and functional group characterizations, followed by the PZQ assay. Thus, considering the solid-state properties, the processing parameters of HME were selected to obtain stable extrudates and an appropriate matrix for PZQ loading.

Praziquantel treatment coverage among school age children against Schistosomiasis and associated factors in Ethiopia: a cross-sectional survey, 2019.

BACKGROUND: World Health Organization estimated that 779 million people are at risk of getting schistosomiasis (SCH) and 240 million people were infected worldwide. SCH due to Schistosoma mansoni (S. mansoni) is a wide public health problem in Ethiopia. The aim of the survey was to quantify national and district disaggregated treatment coverage status for SCH and compare validated coverage with the one reported. METHODS: Community based cross-sectional survey was conducted in April 2019 among households with school age children (SAC) 5-14 years in seven purposively selected districts of the country. Segments to be surveyed were randomly selected and households to be interviewed from each segment were determined using systematic sampling technique. A total of 3378 households visited and 5679 SAC (5-14 years) were interviewed. RESULTS: Overall reported treatment coverage of Praziquantel (PZQ) against SCH was 4286 (75.5%). Males were 27% more likely to swallow the drug (AOR = 1.27; 95% CI: 1.09, 1.47) than females. SAC with age 10-14 years were 45% more likely to swallow the drug compared with their counter parts (5-9 years), (AOR =1.45; 95% CI: 1.25, 1.69). There is statistically significant association between PZQ swallowing status with school enrollment. (AOR = 20.90, 95% CI: 17.41, 25.08). Swallowing status of PZQ against SCH significantly higher for SAC treated in districts applied integrated treatment approach (87.5%) compared with SAC treated in vertical treatment approach (72.5%); P-value < 0.001. SACs were asked for reasons for not taking the drug and the main reported reason for not swallowing PZQ in the present study was none attending of the school. CONCLUSIONS: Over all treatment coverage of PZQ against SCH in the present study was 75.5%. Although it is in accordance with WHO recommendation for Ethiopia, national programmatic improvements are necessary to achieve higher coverage in the future. To increase treatment coverage for PZQ against SCH in Ethiopia, school based training should target all schools. Moreover, mobilization, sensitization and implementation of the community wide treatment need to be improved.

Schistosoma mansoni sarco/endoplasmic reticulum Ca2+ ATPases (SERCA): role in reduced sensitivity to praziquantel.

Praziquantel leads to increase Ca2+ influx and disrupts Ca2+ homeostasis in adult Schistosoma. However, calcium influx is only one component in a series of molecular events leading to the drug effect and some downstream constituents of the cascade that is initiated by this interaction differ between worms with different degrees of susceptibility to praziquantel. Extensive use of the drug raises the concern regarding the selection of drug resistant parasites. SERCA participates in maintenance of Ca2+ homeostasis. Up-regulation of SERCA has been found in Schistosoma mansoni worms with reduced sensitivity to praziquantel. This could be due to increase cytosolic Ca2+, activation of calmodulin kinase II or may be due to SR/ER stress generated from oxidative stress that leads to impaired protein degradation. The significance of SERCA up-regulation is related to counter action of the drug effect by increasing the worm capacity to restore Ca2+ homeostasis, reducing cytosolic Ca2+ followed by lowering mitochondria Ca2+ and consequently inhibition of apoptosis beside its relation to P-glycoprotein. In schistosomes with reduced sensitivity to praziquantel, the agitations produced by Ca2+ influx and the downstream component of the cascade that is initiated by this interaction may be opposed by up-regulation of SERCA and possibly by certain elements of Ca2+ signaling which modulate the process determining cells entrance in the apoptotic state. Revealing the principal mechanisms of up-regulation of SERCA and its significance in reducing the effect of the drug could lead to possible strategies to reverse drug resistance or develop alternative therapies.

Effectiveness of Repeated Administration of Praziquantel with Disodium Glycyrrhizinate and Two Enantiomers of Praziquantel on Opisthorchis felineus (Rivolta, 1884).

BACKGROUND: Nowadays, it is still important to develop effective anti-opisthorchiasis agents. In this work, we tested a complex of praziquantel (PZQ) with a plant origin compound-disodium glycyrrhizinate-in the ratio 1:10 PZQ:Na2GA, containing 11-fold less of the active ingredient. Our aim was to study various ways to treat trematode Opisthorchis felineus with this complex in vitro. Additionally, an in vitro comparison of the anthelmintic action was made among racemic-PZQ, (R)-PZQ, and (S)-PZQ on juvenile and adult maritae of O. felineus. METHODS: Worms extracted from the hamsters were subjected to various regimens of administration of the complex: once a day for 3 days or three times within 1 day. Moreover, mature maritae and juvenile worms of O. felineus were subjected to the comparison the anthelmintic effectiveness of racemic-PZQ, (R)-PZQ, and (S)-PZQ. RESULTS: The O. felineus maritae that received PZQ:Na2GA (1:10) thrice within 1 day were most strongly affected by the drug. Their motility substantially decreased already on the second day after the last dose, and the percentage of live worms by the end of the experimental period was the lowest. These results indicate a cumulative anthelmintic effect of this substance under the regimen "three times within 1 day." For the first time, we report that among the three substances (racemic-PZQ and two enantiomers), (R)-PZQ has the highest anthelmintic activity, toward both juvenile and sexually mature maritae of O. felineus. CONCLUSION: These findings suggest that the development of a supramolecular complex of (R)-PZQ with disodium glycyrrhizinate and administration of this complex three times within 1 day are promising approaches.

Effect of nanoparticles on the therapeutic efficacy of praziquantel against Schistosoma mansoni infection in murine models.

Praziquantel (PZQ) is the main treatment of Schistosomiasis mansoni. However, resistance to it was described. So, there is a necessity to develop novel drugs or to enhance the present drugs. This work aimed to assess the efficacy of PZQ alone and when loaded on liposomes in treatment of S. mansoni infection by parasitological and histopathological studies in experimental murine models. 112 male laboratories bred Swiss Albino mice were used in this work. They were divided into four groups: Group 1: control group; Group 2: infected then treated by PZQ (500 mg/kg) at 7, 30 and 45 days post infection; Group 3: infected then treated by liposome encapsulated PZQ (lip.PZQ) (500 mg/kg) at 7, 30 and 45 days post infection; Group 4: infected then treated by free liposomes at 7, 30 and 45 days post infection. The results showed that G3 caused the highest significant reduction of the total worm count, eggs/gram liver tissue and intestine (97.2%, 99.3%, 99.5%) respectively. Followed by G2 (85.1%, 97.6%, 89.8%) respectively. Regarding the histopathological studies, G3 showed the highest significant reduction in number and diameter of hepatic granuloma (97.6% and 98.1%), followed by G2 (77.2% and 75%) when compared to other groups. In conclusion, lip.PZQ is more effective than free PZQ from all aspects especially when administered 45 days PI.

Role of nanostructures in improvising oral medicine.

The most preferable mode of drugs administration is via the oral route but physiological barriers such as pH, enzymatic degradation etc. limit the absolute use of this route. Herein lies the importance of nanotechnology having a wide range of applications in the field of nano-medicine, particularly in drug delivery systems. The exclusive properties particularly small size and high surface area (which can be modified as required), exhibited by these nanoparticlesrender these structures more suitable for the purpose of drug delivery. Various nanostructures, like liposomes, dendrimers, mesoporous silica nanoparticles, etc. have been designed for the said purpose. These nanostructures have several advantages over traditional administration of medicine. Apart from overcoming the pharmacokinetic and pharmacodynamics limitations of many potential therapeutic molecules, they may also be useful for advanced drug delivery purposes like targeted drug delivery, controlled release, enhanced permeability and retention (EPR) effect. In this review, we attempt to describe an up-to-date knowledge on various strategically devised nanostructures to overcome the problems related to oral drug administration.