Praziquantel

Mechanisms of Praziquantel Resistance

The precise mechanisms by which parasitic helminths develop resistance to this compound are not yet fully characterized. However, research suggests that resistant worms may possess enhanced abilities to metabolize the drug compared to their susceptible counterparts. nih.govlipidmaps.org Investigations into the molecular and cellular adaptations of resistant strains have identified several potential contributing factors, including genetic alterations, modified metabolic pathways, and cellular responses to drug exposure.

Induction and Characterization of Laboratory-Induced Resistance

Laboratory studies have successfully demonstrated the ability to induce this compound resistance in schistosomes, particularly S. mansoni. nih.govlipidmaps.orgfishersci.nofishersci.caguidetopharmacology.orgwikipedia.org A common approach involves exposing parasites to repeated rounds of sub-lethal drug doses, which selects for less susceptible individuals over successive generations. fishersci.nofishersci.ca

Early studies in mice infected with S. mansoni showed that increasing PZQ drug pressure over multiple generations could lead to a population with significantly reduced susceptibility. For instance, one study reported that after seven generations of drug pressure, a high percentage of resistant schistosomes survived a dose that was lethal to most control worms. nih.govlipidmaps.orgfishersci.noguidetopharmacology.orgwikipedia.org Methods for inducing resistance have also been developed using infected snails as an intermediate host. nih.govlipidmaps.org

Characterization of laboratory-induced resistance typically involves comparing the drug sensitivity of selected resistant lines to that of the original susceptible population, often through in vitro or in vivo assays measuring worm survival or recovery after drug exposure. These studies have confirmed that the reduced sensitivity observed in laboratory-selected lines can be heritable, indicating an underlying genetic basis for the resistance. fishersci.ca However, some research has also noted that the characteristics of reduced PZQ sensitivity in laboratory strains can diminish after several generations, even when drug pressure is maintained. nih.govlipidmaps.orgguidetopharmacology.org

Surveillance and Molecular Markers for Field Resistance Detection

Effective surveillance is crucial for the early detection and monitoring of this compound resistance in parasitic helminths. While classical parasitological methods, such as measuring cure rates (CR) and egg reduction rates (ERR) after treatment, have been used, they have limitations in precisely quantifying the level of resistance in natural parasite populations nih.govnih.gov. Low cure rates observed in some areas can be attributed to various factors besides resistance, including intense transmission, high worm burdens, reinfection rates, and the presence of drug-tolerant juvenile worms frontiersin.orgnih.gov.

The development of molecular markers for PZQ resistance has been a significant area of research aimed at improving field surveillance. Identifying the genetic basis of resistance can facilitate the development of tools for directly screening parasite populations for resistance alleles nih.govnih.gov. Until recently, studies on drug resistance were hampered by a lack of known molecular markers associated with PZQ resistance frontiersin.org. However, recent advances in understanding the molecular basis of PZQ action have led to the proposal of several potential resistance markers frontiersin.orgriojournal.com.

Research has implicated the transient receptor potential melastatin ion channel (Sm.TRPMPZQ) as a potential target of PZQ in Schistosoma mansoni. Activation of this channel by PZQ is thought to lead to calcium influx and subsequent paralysis of the worm nih.govriojournal.comfrontiersin.org. Studies have shown that variations in the Sm.TRPMPZQ gene can underlie differences in PZQ response, and identifying specific sequence variants in this gene could provide an approach for monitoring emerging PZQ resistance alleles in the field nih.gov. For instance, a nonsense mutation in Sm.TRPMPZQ resulting in a truncated protein lacking a PZQ binding site has been identified nih.gov.

While morphological techniques, such as observing worm motility or contraction in response to PZQ in vitro, have been used to assess susceptibility, few molecular tools have been widely adopted for the detection of PZQ resistance in the field riojournal.com. Ongoing research aims to screen and validate genes associated with PZQ resistance and develop diagnostic tools for field assessment riojournal.com. Molecular markers are widely used for monitoring drug resistance in other pathogens like malaria parasites and veterinary nematodes, highlighting their potential utility in helminth control programs nih.govbiorxiv.orgwho.int.

Epidemiological and Ecological Factors Influencing Resistance Emergence

The emergence and establishment of this compound resistance in parasitic helminth populations are influenced by a complex interplay of epidemiological and ecological factors. While laboratory studies have successfully induced PZQ resistance in schistosomes through selective pressure, widespread clinical resistance in field populations has not been consistently confirmed frontiersin.orgfrontiersin.orgbiorxiv.org.

Epidemiological factors such as high transmission intensity and high worm burdens can also influence treatment outcomes and potentially mask or contribute to the perception of reduced drug efficacy frontiersin.orgnih.gov. In areas with very intense transmission, rapid reinfection after treatment can lead to low cure rates, even if the drug remains effective against the existing adult worm burden frontiersin.org. The presence of PZQ-tolerant juvenile worms at the time of treatment is another factor that can affect cure rates frontiersin.orgnih.gov.

Ecological factors, including potential selective pressures from concurrent control measures like snail control (for schistosomes), may also play a role nih.gov. Furthermore, the fitness costs associated with resistance alleles in the absence of drug pressure could limit their spread and fixation in the parasite population nih.govoup.com. Some laboratory studies suggest that PZQ-resistant schistosome lines may exhibit reduced cercarial production or other life-history trade-offs compared to susceptible strains, although other studies have shown contrasting results or the ability of resistant isolates to maintain resistance without drug pressure nih.govoup.com.

Structure-Activity Relationship (SAR) Studies of Praziquantel Derivatives

SAR studies are fundamental to understanding how modifications to the this compound structure influence its antiparasitic activity. This knowledge guides the rational design of new compounds with improved properties. nih.govresearchgate.net

Rational Design and Synthesis of Novel this compound Analogues

Rational design and synthesis of novel this compound analogues are driven by the insights gained from SAR studies and a deeper understanding of the drug's potential targets. nih.govresearchgate.netosti.gov This approach involves designing molecules with specific structural features intended to improve potency, broaden the spectrum of activity (including against juvenile worms), overcome resistance mechanisms, or improve pharmacokinetic properties. mdpi.complos.orgasm.org

Researchers are exploring modifications at various positions of the this compound scaffold, including the cyclohexyl ring, the aromatic ring, and the pyrazino-isoquinoline core. plos.orgnih.govmdpi.com The aim is to create compounds that can effectively interact with the proposed molecular targets of this compound, such as the schistosome Transient Receptor Potential Melastatin channel (TRPMPZQ), which has been shown to mirror the SAR of PZQ derivatives. plos.orgnih.govacs.org

Synthetic routes to generate diverse this compound derivatives have been developed to facilitate SAR studies and the identification of promising lead compounds. nih.govresearchgate.net This includes the synthesis of derivatives with altered substituents on the rings, modified linkers, and hybrid molecules incorporating features from other anthelmintic scaffolds. mdpi.comnih.govtandfonline.com

While many synthesized analogues have not surpassed the activity of the parent drug, some have shown promising results in vitro and in vivo, warranting further investigation and optimization. plos.orgmdpi.comnih.gov The rational design process is iterative, with the synthesis and evaluation of new compounds informing subsequent design strategies.

Molecular Hybridization Strategies in Anthelmintic Drug Discovery

Molecular hybridization is a drug design strategy that involves combining structural features from two or more known bioactive compounds into a single molecule. mdpi.comnih.gov This approach aims to create new entities with potentially improved efficacy, broader spectrum, reduced toxicity, or the ability to overcome resistance by targeting multiple pathways. mdpi.comasm.org

In the context of anthelmintic drug discovery, molecular hybridization strategies are being applied to this compound by coupling its core structure or fragments with other pharmacophores known to have antiparasitic activity. mdpi.comnih.govasm.org Given the structural similarities between this compound and certain antimalarial scaffolds like quinolines and isoquinolines, molecular hybrids combining aspects of these structures have been designed and synthesized with the aim of achieving dual antimalarial and antischistosomal activity. mdpi.comnih.gov

Studies have reported the synthesis and evaluation of molecular hybrids of this compound with other moieties, such as cinnamic acids. mdpi.comnih.gov Some of these hybrids have shown notable activity against schistosomiasis in vitro. mdpi.comnih.gov For example, a molecular hybrid bearing a para-isopropyl group on the cinnamic acid moiety exhibited significant activity against S. mansoni schistosomula and adult worms. mdpi.comnih.gov

Molecular hybridization can also involve combining this compound with compounds that have different mechanisms of action to potentially achieve synergistic effects and combat resistance. asm.orgnih.gov This strategy holds promise for developing next-generation anthelmintics with improved efficacy and reduced likelihood of resistance development.

High-Throughput Screening and Lead Compound Identification

High-throughput screening (HTS) plays a crucial role in accelerating the discovery of new anthelmintic lead compounds. nih.govnih.govbiorxiv.org HTS allows for the rapid screening of large libraries of small molecules against parasitic targets or whole organisms to identify compounds with desired activity. nih.govnih.govbeilstein-journals.org

Phenotypic screening, which involves testing compounds against live parasites and observing their effects on motility, development, or survival, is a common HTS approach in anthelmintic drug discovery. nih.govnih.govbiorxiv.orgbeilstein-journals.org Assays based on measuring the motility of parasite larvae or adult worms using techniques like infrared light interference or image analysis have been developed and utilized for HTS campaigns. nih.govnih.govbeilstein-journals.orgresearchgate.net

HTS campaigns have screened hundreds of thousands of compounds to identify potential anthelmintic hits. nih.govnih.gov For example, one study screened 80,500 small molecules against Haemonchus contortus larvae, identifying several hits that inhibited larval motility and/or development. nih.govresearchgate.net Another large-scale screening effort evaluated almost 300,000 compounds against Schistosoma mansoni larvae, identifying a number of promising lead compounds with activity against different life stages. nih.govacs.org

While HTS can identify numerous hits, subsequent lead identification and optimization require further characterization of the active compounds, including confirming their activity, evaluating their potency (e.g., IC50 values), assessing cytotoxicity against mammalian cells, and performing structure-activity relationship studies. nih.govnih.gov HTS is a valuable tool for identifying novel chemical scaffolds with anthelmintic activity that may serve as starting points for the development of new drugs, including those with this compound-like activity or complementary mechanisms.

Repurposing of Existing Compounds with this compound-like Activity

Drug repurposing, also known as drug repositioning, involves finding new therapeutic uses for existing approved drugs. plos.org This strategy can significantly accelerate the drug discovery process because the safety, pharmacokinetic, and manufacturing data for approved drugs are already available. plos.org

In the search for new antischistosomal agents, repurposing existing compounds with potential this compound-like activity or activity against schistosomes through different mechanisms is being explored. plos.orgresearchgate.net Computational approaches, such as in silico screening and chemogenomics strategies, are used to identify approved drugs that may target proteins essential for parasite survival or exhibit structural similarities to known anthelmintics. plos.org

Studies have utilized in silico methods to screen databases of approved drugs and predict potential activity against Schistosoma mansoni. plos.org This has led to the identification of several existing drugs that warrant experimental testing for antischistosomal activity. plos.org

Experimental screening of existing drug libraries against schistosomes has also been conducted. plos.org For instance, screening a collection of approved drugs against S. mansoni juvenile worms identified compounds with antischistosomal activity, including a prophylactic antianginal agent and an antihistaminic drug. plos.org

Repurposing efforts can identify compounds that may not be structurally related to this compound but exhibit similar phenotypic effects on the parasite (e.g., inducing spastic paralysis or tegumental damage) or act on the same molecular target (TRPMPZQ). nih.govacs.org Identifying such compounds can provide alternative treatment options or serve as leads for developing new chemical entities with improved properties compared to this compound. researchgate.net

This compound itself was a result of a repurposing exercise, as it stemmed from a library of compounds initially developed for potential antipsychotic activity before being tested for anthelmintic properties. acs.org This historical success further supports the potential of drug repurposing for discovering new treatments for parasitic diseases.

New Drug Development Pathways for Antischistosomal Agents

The reliance on this compound (PZQ) as the primary treatment for schistosomiasis for decades has highlighted the urgent need for the discovery and development of new antischistosomal agents. Concerns about potential drug resistance and PZQ's limited efficacy against juvenile worms underscore this necessity. frontiersin.orgfrontiersin.orgresearchgate.netfrontiersin.org The drug discovery pipeline for helminth parasites, including schistosomes, has been relatively dry, prompting exploration into various new development pathways. tandfonline.com

One significant avenue involves the screening of diverse compound libraries to identify novel scaffolds with antischistosomal activity. The Medicines for Malaria Venture (MMV), in collaboration with initiatives like the Drugs for Neglected Diseases Initiative (DNDi), has made compound libraries available for screening against schistosomes. tandfonline.commmv.orgmmv.orgnih.govresearchgate.net For instance, screening the MMV Pathogen Box, containing 400 drug-like compounds, against Schistosoma mansoni has identified promising hits active against both newly transformed schistosomula (NTS) and adult worms. nih.govresearchgate.net Compounds like MMV1581558 and nitazoxanide have shown notable in vitro activity against adult S. mansoni. researchgate.net Further in vivo testing of selected compounds from these screens has revealed candidates with significant worm burden reductions in mouse models. nih.govresearchgate.net

Drug repurposing or repositioning is another practical approach being actively pursued. researchgate.netplos.org This involves screening existing approved drugs or compounds that have been part of clinical trials for activity against schistosomes. researchgate.netplos.org This strategy can accelerate the drug discovery process by starting with compounds with known safety profiles. researchgate.net High-content screening (HCS) approaches have been successfully employed to screen libraries of approved compounds, identifying new potential drug candidates and creating phenotypic profiles of known schistosomicidal agents. frontiersin.org

Molecular modeling approaches, including structure-based drug design and ligand-based drug design, are also integral to identifying new drug candidates and understanding their interactions with schistosome targets. researchgate.net Integrated in silico methods are being used to identify potential inhibitors of key schistosome enzymes, such as thioredoxin glutathione reductase (SmTGR), which is crucial for the parasite's redox metabolism. mdpi.com Studies have identified alkaloids, such as lindoldhamine and daibucarboline A, as potential SmTGR inhibitors, highlighting the role of natural products in drug discovery. mdpi.com

Research into the molecular basis of PZQ action and resistance continues to inform the development of new agents. While the exact mechanism of PZQ is still being fully elucidated, it is understood to involve the activation of the transient receptor potential ion channel (Sm.TRMPPZQ) in the worm, leading to calcium influx and paralysis. frontiersin.orgnih.govbiomedcentral.com Understanding potential resistance mechanisms, such as enhanced drug metabolism or genetic variations in ion channels, is vital for designing compounds that can circumvent these issues. frontiersin.orgnih.gov

Beyond PZQ analogues, other classes of compounds are being investigated. Artemisinin derivatives, primarily known for their antimalarial activity, have demonstrated potent antischistosomal properties, particularly against juvenile worms. cabidigitallibrary.orgresearchgate.netwikipedia.orgmdpi.comengineering.org.cn Although their exact mechanism against schistosomes is not fully described, it is thought to involve the cleavage of the endoperoxide moiety and the generation of reactive oxygen species. cabidigitallibrary.orgresearchgate.netmdpi.comengineering.org.cn Clinical trials are needed to provide unambiguous evidence of their therapeutic value against schistosomiasis in humans. researchgate.netmdpi.com

Oxamniquine, another historical treatment for S. mansoni, provides a model for drug discovery and repurposing, particularly through structure-activity relationship (SAR) studies and X-ray crystallographic data to develop new derivatives with broader species activity. tandfonline.comnih.gov

Novel drug targets within schistosomes are also being actively explored using genome-scale studies and bioinformatic approaches. nih.govbiorxiv.org Identifying essential genes and proteins within schistosomes that are similar to known drug targets in humans or other organisms can provide starting points for the development of targeted therapies. nih.govbiorxiv.org For example, a genome-wide study in S. mansoni identified a parasite p97 ortholog as a potential drug target, leading to the discovery of inhibitors that disrupt the ubiquitin proteasome system in schistosomes. nih.govbiorxiv.org Peptidases are also considered potential drug targets due to their involvement in critical parasite processes. biorxiv.org

The development of new drug delivery systems, particularly using nanotechnology, is being explored to improve the efficacy and safety profile of existing and new antischistosomal drugs, focusing significantly on PZQ due to its current clinical use. ijpsat.org

The following table summarizes some of the compounds and targets discussed in the context of new antischistosomal drug development pathways:

Despite ongoing research and the identification of promising candidates and targets, there is a recognized need for a clearer scientific framework for conducting screening studies and a continued effort to advance compounds through the preclinical and clinical development pipeline to provide much-needed alternatives to this compound. tandfonline.comresearchgate.net

In Vitro Parasite Culture Systems for Praziquantel Efficacy Assessment

In vitro culture systems play a vital role in the initial assessment of this compound's effects on schistosomes and other flatworms. These systems allow researchers to directly expose different life stages of the parasite to varying concentrations of the drug and observe the resulting morphological and physiological changes. Studies have utilized in vitro methods to evaluate the schistosomicidal effects of this compound against adult worms, observing effects such as decreased muscle contraction, decreased tegumental disruption, and decreased calcium influx frontiersin.org.

In vitro methods have also been developed and validated for assessing drug sensitivity on juvenile developmental stages of Schistosoma mansoni, aiming to reduce the reliance on animal models nih.gov. These methods have shown that in vitro developed S. mansoni worms exhibit similar drug sensitivity to this compound as worms recovered from rodents across various life stages, although slightly lower activity was observed at 21 days of development in vitro compared to in vivo nih.gov.

In vitro studies have also explored the synergistic effects of this compound when combined with other drugs. For instance, combinations of amiodarone with this compound demonstrated synergistic activity against Schistosoma mansoni adult worms in vitro asm.org. Similarly, sublethal doses of this compound combined with omeprazole significantly increased worm mortality in vitro, suggesting a synergistic effect plos.org.

In vitro culture systems are also used for evaluating this compound against other flatworms, such as the eye fluke Philophthalmus palpebrarum and Taenia solium cysts ekb.egasm.org. Studies on P. palpebrarum adult worms in vitro have determined the lethal concentrations (LC50 and LC90) of this compound, showing dose- and time-dependent mortality ekb.eg. For Taenia solium cysts, in vitro culture allows for the assessment of drug activity based on morphological changes and the inhibition of parasite-derived alkaline phosphatase release asm.org.

Rodent Models for Schistosomiasis Research and Drug Evaluation

Rodent models, particularly mice, are extensively used for studying schistosomiasis and evaluating the in vivo efficacy of this compound. These models allow for the investigation of the complex interactions between the host and the parasite, as well as the pharmacokinetics and pharmacodynamics of the drug.

Alternative Model Organisms in this compound Research

Beyond schistosomes and traditional rodent models, alternative model organisms are employed to investigate specific aspects of this compound's effects, particularly its mode of action and potential for resistance.

Advanced Imaging and Microscopy Techniques in this compound Studies

Advanced imaging and microscopy techniques have been instrumental in elucidating the effects of this compound (PZQ) on parasitic helminths, particularly schistosomes, at a detailed structural and functional level. These techniques provide visual evidence of drug-induced changes, complementing biochemical and physiological studies.

Scanning electron microscopy (SEM) has been widely used to examine the ultrastructure of the parasite tegument following PZQ treatment. Studies on Schistosoma haematobium have shown that this compound administration leads to various structural changes in the tegument, including the appearance of blebs and spine deformities as early as half an hour after exposure. nih.gov Changes such as generalized deformities, loss of spines, and tegumental swellings were also observed when the drug was administered prior to worm maturation. nih.gov Similarly, SEM studies on Schistosoma mansoni have revealed extensive tegumental damage, characterized by the rupture of tubercles and loss of spines in male worms, and ulceration in female worms. researchgate.net These observations highlight the significant disruptive impact of PZQ on the parasite's outer covering. The tegument of Schistosoma mansoni worms treated with PZQ showed shrinkage of the outer surface and marked loss of spines in male worms, with mild ulceration in the female tegument. researchgate.net Compared to other substances tested in one study, PZQ demonstrated superior antiparasitic effects on S. mansoni worms, causing extensive tegumental damage. researchgate.net Another study using SEM on Schistosoma mansoni treated in vivo with PZQ noted that the drug more pronouncedly affected the surface of male worms than females. nih.gov PZQ was found to be more effective in destroying spined papillae, causing wrinkling, and disturbing the interpapillar spaces. nih.gov

Confocal laser scanning microscopy (CLSM) is another valuable tool employed in PZQ research. CLSM allows for the visualization of parasite structures and the localization of fluorescently labeled molecules within the parasite. This technique has been used to examine alterations on the tegumental surface of Schistosoma mansoni schistosomula, revealing extensive tegumental destruction, including blebbing, granularity, and a shorter body length following exposure to certain compounds, including comparisons to PZQ's effects. nih.gov Confocal fluorescence microscopy has also been utilized with fluorescent derivatives of this compound to investigate the drug's interaction with Schistosoma japonicum cercariae. nih.gov These studies have shown that a fluorescent PZQ derivative (PZQ-5) is biocompatible and cell-permeable, localizing mainly at the cercarial tegument, which correlates with the death of cercariae over time. nih.gov CLSM has also been explored as a diagnostic tool to visualize Schistosoma mansoni eggs directly within the gut of infected mice, permitting the classification of egg viability and differentiation between schistosomal species. plos.org

Beyond electron and confocal microscopy, other advanced imaging techniques contribute to understanding PZQ's effects. Intravital microscopy (IVM) allows for the direct visualization of live schistosomes within the blood vessels of anesthetized host animals, providing insights into the drug's impact on parasite motility and location in vivo. nih.gov Fluorescence Molecular Tomography (FMT) is another non-invasive imaging method used to monitor schistosomes in vivo by detecting fluorescent tracers taken up by the parasites, enabling the documentation of the decline in parasite numbers following PZQ treatment in infected mice. nih.gov, nih.gov Atomic force microscopy (AFM), which provides high-resolution 3D surface topography, has been used in parasite research to examine surface structures and molecular interactions uni-wuerzburg.de, mdpi.com, and while not exclusively focused on PZQ in the search results, it holds potential for detailed analysis of PZQ-induced tegumental changes at the nanoscale. aucegypt.edu, researchgate.net, diamond.ac.uk Super-resolution microscopy techniques, such as 3D-SIM, offer spatial resolution beyond the diffraction limit of conventional light microscopy ous-research.no, mdpi.com, which could provide finer details of PZQ's effects on parasite cellular structures and protein localization.

These advanced imaging modalities collectively provide crucial visual data on the morphological and structural consequences of this compound treatment on parasitic worms, contributing to a deeper understanding of its anthelmintic mechanisms.

Data from selected studies employing microscopy techniques:

Clinical Trial Design and Methodologies for Praziquantel Studies

Clinical trials investigating this compound efficacy in treating schistosomiasis utilize a range of designs and methodologies to assess its impact on parasite infection. A systematic review and meta-analysis of this compound trials identified 273 studies, of which 55 were deemed eligible for analysis, involving nearly 20,000 subjects. plos.orgnih.govresearchgate.netnih.gov These studies were conducted across numerous countries and sites, with a significant proportion focusing on school-aged children in Africa infected with Schistosoma mansoni. plos.orgnih.govresearchgate.netnih.gov

Standard clinical trial designs and technical protocols are often employed, although parasitological methods for assessing therapeutic efficacy can vary depending on the Schistosoma species. who.intnih.gov

Efficacy of this compound Against Different Schistosoma Species

This compound is recognized for its broad-spectrum activity against all major Schistosoma species that infect humans: Schistosoma mansoni, S. haematobium, S. japonicum, S. mekongi, and S. intercalatum. asm.orgcdc.govmedscape.comviamedica.plnih.gov However, the efficacy of this compound, as measured by cure rates and egg reduction rates, can vary among these species. plos.orgnih.govresearchgate.netnih.govplos.orgplos.orgnih.gov

Studies and meta-analyses consistently indicate that this compound is highly efficacious against S. japonicum, often achieving higher cure rates compared to S. mansoni and S. haematobium with the standard dose. plos.orgnih.govresearchgate.netnih.govnih.gov For instance, a meta-analysis reported a CR of 94.7% for S. japonicum with the 40 mg/kg dose, compared to 77.1% for S. haematobium and 76.7% for S. mansoni. plos.orgnih.govresearchgate.netnih.gov

While cure rates may differ, this compound generally achieves high egg reduction rates (typically >80-90%) across the different species, significantly reducing the intensity of infection. plos.orgnih.govresearchgate.netnih.govplos.orgplos.orgnih.gov

Table summarizing comparative efficacy against major species (based on pooled data from studies):

Note: Ranges are approximate and can vary based on study population, intensity of infection, and diagnostic methods.

The reasons for the observed differences in efficacy among species are not fully understood and warrant further investigation.

Efficacy Against Various Parasite Developmental Stages

This compound's efficacy is known to be stage-dependent, with the drug being most effective against the adult stages of the schistosome worm. plos.orgnih.govasm.orgcdc.govviamedica.plmedrxiv.orgresearchgate.net Immature worms (schistosomula) are generally considered less susceptible to this compound treatment. nih.govasm.orgviamedica.plmedrxiv.orgresearchgate.netd-nb.info

This differential susceptibility to developmental stages has implications for treatment strategies and follow-up. If individuals are infected with a significant number of immature worms at the time of treatment, these worms may survive and mature later, leading to a lower observed cure rate, even if the adult worms were eliminated. plos.orgnih.govd-nb.info This is one of the reasons why follow-up assessments are typically conducted several weeks post-treatment, allowing time for any surviving immature worms to mature and start producing eggs. researchgate.net

Some studies suggest that this compound may have some effect on schistosome eggs lodged in tissues, but its primary action is on the adult worms. cdc.gov The drug's effect on adult worms leads to their detachment from the host's blood vessel walls and subsequent clearance.

Influence of Host Factors on this compound Efficacy

Age: Age has been identified as a factor influencing this compound efficacy, particularly when considering cure rates. plos.orgplos.org Some studies suggest that cure rates may be higher in adults compared to children. plos.org Differences in drug metabolism and pharmacokinetics between age groups, such as the maturation of hepatic enzymes, may contribute to these variations. plos.orgfrontiersin.org

Intensity of Infection: The pre-treatment intensity of infection, often measured by the number of eggs per gram of stool or per 10 ml of urine, can impact treatment outcomes. medscape.commdpi.com Individuals with heavy infections may have lower cure rates compared to those with light infections. mdpi.com However, this compound is generally very effective at reducing egg counts regardless of the initial infection intensity. mdpi.commdpi.com

Host Immune Response: The host's immune response to the parasite may play a role in the effectiveness of this compound. cdc.govviamedica.pl A mature antibody response to the parasite is thought to be required for the drug to exert its full effect. cdc.gov Differences in immune responses between individuals, or in lightly infected patients who may have a less robust immune response, could potentially influence treatment success. cdc.gov

Reinfection: In endemic areas, reinfection after successful treatment is common and can affect observed cure rates in follow-up studies, especially long-term ones. plos.orgnih.govjams.pubasm.orgmedscape.com Apparent treatment failures or low cure rates in such settings may be due to rapid reinfection rather than a lack of drug efficacy or drug resistance. plos.orgnih.govfrontiersin.org Long follow-up times increase the likelihood of reinfection influencing the results. plos.orgnih.gov

Understanding the interplay of these host factors is important for optimizing treatment strategies and interpreting efficacy data in diverse populations and epidemiological settings.

Praziquantel's Impact on Host Immune Responses to Parasitic Infections

This compound treatment significantly influences the host immune response to schistosome infections. Studies have shown that PZQ treatment leads to the clearance of infection and is associated with elevated antigen-specific proliferation and cytokine production. oup.complos.org The drug's efficacy in vivo requires the engagement of the host immune system. plos.org Following PZQ exposure, sexually mature worms experience damage to their tegument surface, which exposes parasite antigens to the host humoral immune system and triggers the recruitment of innate immune cells involved in parasite elimination. plos.org PZQ is less effective at clearing infections in immunocompromised animal models, such as those deprived of T-cells and B-cells, highlighting the importance of the host immune response. plos.org

Treatment with PZQ can alter parasite-specific cellular and humoral responses, particularly in children. nih.gov These treatment-induced changes have been linked to resistance to subsequent re-infection. nih.govnih.gov It has been hypothesized that PZQ treatment, by damaging the worm's tegument, exposes previously hidden parasitic antigens, making the parasite vulnerable to host immune defenses. frontiersin.orgnih.gov This exposure of worm surface antigens follows the rapid damage to the schistosome tegument caused by this compound. nih.gov This interaction of PZQ with schistosomes results in both quantitative and qualitative changes in host-parasite-specific immune responses. nih.gov

Changes in Cytokine Profiles Post-Treatment

This compound treatment induces significant changes in the host's cytokine profiles. In individuals infected with Schistosoma haematobium, removal of the infection through PZQ treatment resulted in increased schistosome-specific cytokine responses. oup.com These increases were negatively associated with CD4+CD25+FOXP3+ T-cells and accompanied by an increased frequency of effector memory T-cells. oup.com

Studies in children infected with schistosomiasis have evaluated the cytokine profiles of IL-4, IL-2, IL-10, IL-5, IFN-γ, and TNF in serum samples before and after treatment. Analysis indicated a shift in cytokine expression after treatment, with a general trend of decrease in the expression of most cytokines at six and twelve weeks post-treatment compared to pretreatment levels, except for TNF. researchgate.netnih.gov Statistically significant differences were observed in the expression of IL-2, IL-4, IL-10, IFN-γ, and IL-5. researchgate.netnih.gov The reduction in cytokine levels is directly related to PZQ's influence, which modulates the cytokine response by eliminating adult worms, reducing parasitic load, and decreasing morbidity. researchgate.netnih.gov

In Schistosoma mansoni infection, treatment with either this compound or oxamniquine showed similar effects on cytokine production. nih.gov Before treatment, infected groups often showed low ratios of IL-4:IFN-γ, IL-5:IFN-γ, and IL-10:IFN-γ, indicating high IFN-γ levels in infected individuals. Post-treatment, a general increase in immunomodulation was observed with elevated immune reactivity and cytokine production. nih.gov Significant increases in levels of IL-4, IL-5, and IL-10 cytokines were induced by treatment at 6 and 18 weeks after treatment. nih.gov

Increases in human T helper 2 (Th2) cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by PZQ treatment. Levels of Schistosoma mansoni-induced IL-4 and IL-5, along with post-treatment levels of immunoglobulin E recognizing the parasite's tegument, correlate with human resistance to subsequent re-infection after treatment. oup.com Levels of soluble worm antigen (SWA)-induced IL-4, IL-5, IL-10, and IL-13 increased after PZQ treatment, with the greatest relative increases seen in responses to tegument (Teg) antigens. oup.com Mean levels of Teg-specific IL-5 and IL-10 increased significantly, as did mean levels of IL-13. oup.com Levels of SEA-, SWA-, and Teg-induced interferon-γ were not significantly changed by treatment. oup.com

In a baboon model of schistosomiasis, the cytokine expression profile of PBMCs following PZQ therapy showed a mixed Th1/Th2/Th17 response, with nearly all measured cytokines upregulated compared to the chronic disease stage, except for TGF-β which was downregulated, and TNF-α and IL-6 which showed no significant change. frontiersin.org

While some studies show a decrease in certain cytokine levels post-treatment, others report increases in antigen-specific responses. This difference may depend on the specific cytokines measured, the antigens used for stimulation, the time points of evaluation, and the host species or age group studied. For instance, one study showed a decrease in IL-4 and IL-10 post-treatment, while another reported an increase in these cytokines following SEA stimulation in circulating lymphocytes. nih.gov

The changes in cytokine production post-treatment are summarized in the following table based on findings from various studies:

Gene Expression and Transcriptome Analysis in Parasites Upon this compound Exposure

Transcriptomic analysis has provided valuable insights into the molecular responses of schistosomes to this compound exposure. Studies using RNA sequencing (RNA-Seq) and microarray analysis have revealed drug-evoked changes in gene expression in Schistosoma mansoni and Schistosoma japonicum. plos.orgplos.orgresearchgate.net

In Schistosoma mansoni, in vivo PZQ exposure leads to transcriptional changes, including the upregulation of putative immunomodulatory and anticoagulant gene products. plos.orgbiorxiv.org Some of these gene products, such as Kunitz-type protease inhibitors, localize to the worm esophagus and may be secreted into the host circulation, potentially reflecting parasite mechanisms of immune-evasion in response to chemotherapy. plos.orgbiorxiv.org One such isoform, SmKI-1, has demonstrated immunomodulatory and anti-coagulant properties. plos.org Transcriptional changes in S. mansoni following in vivo PZQ exposure appear to occur relatively late, around 12 hours after drug administration, corresponding to the period after the parasite shifts to the liver. plos.org The transcriptional response to in vivo PZQ exposure is similar between immature (4-week-old) and mature (7-week-old) parasites, although mature parasites show greater changes in gene expression. plos.org

Transcriptome-wide microarray analysis of adult Schistosoma japonicum perfused from infected mice after oral administration of sub-lethal doses of PZQ revealed differential gene expression influenced by the sex of the parasite. plos.orgresearchgate.net In male parasites, genes initially upregulated were associated with "Tegument/Muscle Repair" and "Lipid/Ion Regulation" functions, followed by "Drug Resistance" and "Ion Regulation" associated genes. plos.orgresearchgate.net In female worms, prominent responses included the upregulation of "Ca2+ Regulation" and "Drug Resistance" genes, and later transcripts related to "Detoxification" and "Pathogen Defense" mechanisms. plos.orgresearchgate.net

Studies have also investigated the transcriptional responses of schistosomes with reduced sensitivity to this compound. Analysis of differentially regulated transcripts in a laboratory strain of S. mansoni with diminished susceptibility to PZQ did not clearly point to a single gene product or pathway associated with drug resistance, suggesting the possibility of either a loss of function mutation to a single gene or an epistatic interaction of multiple gene products. nih.gov However, recent genetic analysis has implicated a transient receptor potential (TRP) channel, Sm.TRPMPZQ, in the variation of PZQ responses in S. mansoni. nih.govfrontiersin.org This channel is activated by nanomolar concentrations of PZQ. nih.gov Resistant parasites have shown lower expression of Sm.TRPMPZQ compared to sensitive parasites. nih.govfrontiersin.org

Long non-coding RNAs (lncRNAs) are also modulated in Schistosoma mansoni following in vivo PZQ exposure. Re-analysis of RNA-Seq data revealed hundreds of lncRNAs differentially expressed after PZQ exposure in both mature and immature worms, indicating an extensive reprogramming of gene expression beyond protein-coding genes. mdpi.com

The mating status of female worms can also influence PZQ-driven transcriptional changes. Studies have identified sets of genes affected by PZQ in both paired and unpaired mature female S. mansoni, sometimes with opposite gene expression patterns, highlighting the influence of mating status on the drug's effects. researchgate.net

Key findings from parasite transcriptome analysis upon PZQ exposure include:

Upregulation of immunomodulatory and anticoagulant genes in S. mansoni. plos.orgbiorxiv.org

Sex-specific gene expression changes in S. japonicum, with roles in tegument/muscle repair, ion regulation, drug resistance, detoxification, and pathogen defense. plos.orgresearchgate.net

Involvement of the Sm.TRPMPZQ channel in PZQ response variation and resistance, with lower expression in resistant parasites. nih.govfrontiersin.org

Modulation of long non-coding RNAs in S. mansoni after PZQ exposure. mdpi.com

Influence of female worm mating status on PZQ-induced transcriptional changes. researchgate.net

Host Transcriptomic Signatures Associated with Treatment Outcomes

While the provided search results offer significant detail on parasite transcriptomic changes and host immune responses (including cytokine profiles), there is limited direct information specifically detailing host transcriptomic signatures associated with this compound treatment outcomes in the context of schistosomiasis.

One study examined immune and transcriptome profiles in Schistosoma haematobium-infected schoolchildren before and after this compound treatment. At the transcriptome level, schistosome infection was associated with enrichment in cell adhesion, while parasite removal was associated with a more quiescent profile. oup.comresearchgate.net Further analysis indicated that alteration in cellular energy metabolism was associated with S. haematobium infection and that early growth response genes 2 and 3 (EGR2 and EGR3), transcription factors that negatively regulate T-cell activation, may play a role in adaptive immune hyporesponsiveness. oup.comresearchgate.net This suggests that changes in the host transcriptome, particularly in genes related to immune regulation and cellular metabolism, occur following successful treatment and resolution of infection-associated hyporesponsiveness.

Another study, while not focused on schistosomiasis, investigated host transcriptomic signatures as an alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV. whiterose.ac.uk This study highlighted that in immunocompromised individuals, host immune response restoration is pivotal for treatment efficacy, and transcriptomic signatures in peripheral blood may reflect immunological responses underpinning parasite clearance or persistence. whiterose.ac.uk This provides a general principle that host transcriptomic profiles can be indicative of treatment outcomes in parasitic infections, although specific research detailing such signatures directly linked to this compound treatment outcomes in schistosomiasis was not extensively found in the provided search results.

The available information suggests that successful this compound treatment leads to a shift in the host immune landscape, moving away from the hyporesponsive state associated with chronic infection towards a more responsive profile. This shift is reflected in changes in cytokine production and potentially in the broader host transcriptome, particularly in genes involved in immune cell function and metabolism. However, specific host transcriptomic signatures that reliably predict or correlate with this compound treatment outcomes in schistosomiasis require further dedicated research.

Integration of Omics Technologies (Genomics, Proteomics, Metabolomics)

Omics technologies, including genomics, proteomics, and metabolomics, are increasingly being applied to understand the complex interactions between Schistosoma parasites and their hosts, as well as the effects of praziquantel at a molecular level. These approaches aim to identify potential drug targets, understand mechanisms of resistance, and discover biomarkers for diagnosis and treatment monitoring.

Genomic studies of Schistosoma species provide insights into the parasite's biology and potential vulnerabilities. Transcriptomics and proteomics can reveal changes in gene and protein expression in response to this compound treatment or in resistant strains, helping to elucidate the drug's mechanism of action and resistance mechanisms. For instance, comparative proteomic analysis of this compound-susceptible and -resistant Schistosoma mansoni has revealed distinct responses between male and female worms, highlighting potential sex-specific mechanisms of resistance or drug action. frontiersin.org Early immunomics work utilized techniques like 2D Western blotting and mass spectrometry to identify and compare proteins recognized by serum samples from S. haematobium-exposed patients before and after this compound treatment. nih.gov This approach, combining proteomics with serology, aims to understand the interaction between the host immune system and parasite antigens. nih.gov

Metabolomics studies investigate the metabolic changes in the host or parasite following infection or treatment. Analyzing small endogenous peptides in biological samples through "peptidomics," a subfield of proteomics, can help identify disease-related biomarkers. universiteitleiden.nl Multi-omics sequencing technology has been used to analyze the dynamic changes of the intestinal microbiome in mice infected with Schistosoma japonicum after intervention with Bacillus amyloliquefaciens, revealing connections to host metabolism. plos.org Such studies can provide new insights into potential adjuvant therapies or strategies to modulate the host-microbiome interaction to improve schistosomiasis control. plos.org

Advanced Computational Approaches (Molecular Docking, Network Pharmacology, AI)

Advanced computational approaches, such as molecular docking, network pharmacology, and artificial intelligence (AI), are accelerating the discovery and development of new antischistosomal agents and understanding the mechanisms of existing ones like this compound.

Molecular docking is used to predict the binding affinity and orientation of drug candidates, including this compound derivatives, to target proteins in the parasite. tandfonline.complos.org This helps in the rational design of new compounds with improved efficacy or reduced potential for resistance. For example, molecular docking studies have been employed to screen phytochemicals for inhibitory activity against Schistosoma mansoni Histone Deacetylase 8 (SmHDAC8), a promising therapeutic target. mdpi.com

Network pharmacology takes a holistic approach by analyzing the complex interactions between drugs, targets, and biological pathways within the host and parasite. tandfonline.com This can help to understand the multifactorial nature of schistosomiasis and identify potential synergistic drug combinations or novel targets. Studies have utilized network pharmacology to explore parasite biology, disease mechanisms, and potential treatments, identifying this compound and its derivatives as key drugs. tandfonline.com

AI and machine learning are being integrated into drug discovery pipelines to analyze large datasets from omics studies and high-throughput screening, predict drug efficacy and toxicity, and identify novel drug candidates. nih.gov These approaches can significantly reduce the time and cost associated with traditional drug development. The integration of network pharmacology, machine learning, molecular docking, and molecular dynamics simulations is being used to explore the mechanisms of traditional Chinese medicine in treating schistosomiasis, demonstrating the power of these combined computational methods. researchgate.net

Combination Therapies and Drug Synergism Research

Research into combination therapies involving this compound and other drugs is a key strategy to improve treatment outcomes, overcome this compound limitations, and potentially mitigate the development of resistance. Combining this compound with drugs that have different mechanisms of action can lead to synergistic effects, where the combined effect is greater than the sum of the individual drug effects.

Studies have investigated the synergistic effects of this compound in combination with various compounds. For example, the combination of this compound with the patented compound DW-3-15 showed strong synergism against Schistosoma japonicum in vitro, resulting in significantly reduced viability of schistosomes. nih.gov In vivo studies also demonstrated improved schistosomicidal efficacy with this combination compared to monotherapy. nih.gov

Combinations of this compound with other anthelmintics, such as oxamniquine derivatives, have shown promise in overcoming this compound treatment limitations, including efficacy against this compound-resistant parasites and immature stages. biorxiv.org Treatment with a co-dose of this compound and CIDD-0150303, an oxamniquine derivative, reduced the worm burden of this compound-resistant parasites in an animal model by 90.8%. biorxiv.org

Combination therapies with antimalarial drugs like mefloquine and artemether have also been explored, showing synergistic or additive effects in rodent studies, even allowing for reduced this compound doses while maintaining efficacy. plos.org However, not all combinations are synergistic; studies have shown no beneficial synergistic or additive action with combined treatments of this compound and drugs like clonazepam and metrifonate. plos.org Further research is needed to identify optimal drug combinations, dosages, and formulations, as well as to consider potential drug interactions and the risk of resistance development to the partner drug, particularly in regions where malaria is prevalent. viamedica.pl

Here is a table summarizing some combination therapy research findings:

Strategies for Overcoming Current this compound Limitations

Despite its widespread use and effectiveness, this compound has limitations, including limited efficacy against juvenile schistosomes and the potential for the development of drug resistance. nih.govfrontiersin.org Strategies to overcome these limitations are crucial for the long-term control and potential elimination of schistosomiasis.

One key strategy is the development of new drugs or derivatives that are effective against all life stages of the parasite, including the immature forms that are less susceptible to this compound. biorxiv.orgfrontiersin.org Research into oxamniquine derivatives, for example, has identified compounds effective against immature stages and this compound-resistant strains. biorxiv.org

Another strategy involves enhancing the efficacy of this compound through novel formulations or delivery methods that improve its pharmacokinetic properties and ensure adequate drug exposure at the site of infection. Understanding the drug metabolism and pharmacokinetics of this compound is important for addressing variable drug exposure during treatment. plos.org

Addressing the concern of drug resistance is paramount. While widespread clinical resistance remains rare, laboratory studies have demonstrated the possibility of inducing resistance in Schistosoma mansoni. scielo.br Research is focused on understanding the molecular mechanisms of resistance to identify ways to circumvent it. This includes studying genetic and proteomic differences between susceptible and resistant strains. frontiersin.org Continued monitoring of drug quality is also essential to ensure the effectiveness of this compound and detect potential cases of suspected resistance. frontiersin.orgnih.gov

Furthermore, combining chemotherapy with other control measures, such as snail control, improved sanitation, and health education, is considered essential for reducing transmission and the reliance on mass drug administration alone, which can exert selection pressure for resistance. frontiersin.orgnih.govnih.gov

Global Health Challenges and Research Priorities in Schistosomiasis Control

Schistosomiasis remains a significant global health challenge, particularly in tropical and subtropical regions with limited access to clean water and sanitation. plos.orgviamedica.plastellas.com While large-scale treatment programs using this compound have significantly reduced prevalence and morbidity in many areas, achieving elimination requires a multi-faceted approach and sustained research efforts. who.intwho.int

One major research priority is the development of new, safe, and effective antischistosomal drugs with novel mechanisms of action to reduce the reliance on this compound and combat potential resistance. mdpi.comnih.govresearchgate.net This includes exploring new chemical entities, repurposing existing drugs, and investigating natural products. mdpi.commdpi.com

Another critical priority is the development of a pediatric formulation of this compound suitable for preschool-aged children, who are a significant at-risk group. astellas.comwho.int The development of a 150 mg dispersible tablet is a significant step in addressing this need. astellas.com

Improving diagnostic tools is also a key research priority. Current methods, primarily based on egg detection, lack sensitivity, especially in low-intensity infections, which hinders accurate mapping of endemic areas and monitoring of control programs. viamedica.pl Research is needed to develop more sensitive, specific, and cost-effective diagnostic techniques, including molecular diagnostics and biomarker-based assays. nih.govviamedica.pl

Furthermore, research is needed to better understand the long-term impact of repeated this compound treatment, the dynamics of transmission in different ecological settings, and the most effective strategies for integrating chemotherapy with other public health interventions like WASH (Water, Sanitation, and Hygiene) programs and snail control. nih.govwho.int Addressing these global health challenges requires continued investment in research and strong international collaboration. nih.govastellas.com

Q. What are the primary mechanisms of action of praziquantel against schistosomes, and how are these mechanisms experimentally validated?

this compound (PZQ) induces rapid calcium influx in schistosomes, leading to paralysis and tegumental damage. Experimental validation involves:

• In vitro Ca²⁺ flux assays : Measuring intracellular calcium levels using fluorescent reporters in adult worms exposed to PZQ .
• Cytochalasin D studies : Demonstrating that cytoskeletal disruption prevents PZQ-induced Ca²⁺ influx and worm death, suggesting actin-dependent drug uptake .
• Tegumental analysis : Scanning electron microscopy (SEM) to visualize PZQ-induced blebbing and disruption of the parasite surface .

Q. How does the stereochemistry of this compound influence its efficacy and safety profile?

The (R)-enantiomer is therapeutically active, while the (S)-enantiomer is ineffective and contributes to bitter taste and toxicity. Methodological approaches include:

• Chiral resolution : Classical resolution via diastereomeric salt formation or enzymatic methods to isolate (R)-PZQ .
• In vivo efficacy testing : Comparing cure rates in animal models (e.g., rabbits infected with S. japonicum) treated with racemic PZQ vs. enantiomerically pure (R)-PZQ .
• Toxicity assays : Evaluating mutagenic potential using Syrian hamster embryo cell transformation assays for racemic vs. resolved forms .

Q. What statistical methods are appropriate for analyzing this compound treatment efficacy in field studies?

Key methodologies include:

• Cluster-adjusted logistic regression : Adjusting for within-school clustering in mass drug administration (MDA) trials to calculate odds ratios for treatment uptake .
• Egg reduction rate (ERR) analysis : Comparing geometric mean egg counts pre- and post-treatment, with 95% confidence intervals .
• Missing data handling : Using robust standard errors and assuming data is missing completely at random (MCAR) in multivariable models .

Advanced Research Questions

Q. What experimental approaches are used to investigate this compound resistance in Schistosoma spp.?

• Functional genomics : CRISPR/Cas9 mutagenesis of Sm.TRPMPZQ (a putative PZQ target) to assess channel sensitivity via Ca²⁺ reporter assays. Mutants like p.Y1554C and p.Q1670K show complete loss of PZQ sensitivity (EC₅₀ > 10 μM vs. wild-type EC₅₀ = 0.74 μM) .
• Population genomics : Haplotype diversity analysis using integrated haplotype scores (iHS) to detect selection signals in endemic regions (e.g., Lake Victoria, Uganda) .
• In vitro dose-response assays : Measuring EC₅₀ values across PZQ-resistant and susceptible parasite isolates .

Q. How can pharmacokinetic variability in this compound response be addressed in pediatric formulations?

• Enantiomer-specific pharmacokinetics : Developing (R)-PZQ monotherapy to reduce dose size and improve palatability. Studies show (R)-PZQ has 2x higher bioavailability than racemic PZQ in preclinical models .
• Population pharmacokinetic modeling : Using nonlinear mixed-effects models to account for age-dependent metabolic differences (e.g., cytochrome P450 activity) .
• Pediatric formulation trials : Testing orally disintegrating tablets (ODTs) or liquid suspensions in children aged 3–6 years, with pharmacokinetic sampling at 0–24 hours post-dose .

Q. What genomic and functional evidence exists for TRPMPZQ receptor mutations affecting this compound sensitivity?

• Variability mapping : Sequencing Sm.TRPMPZQ in 570 S. mansoni isolates identified 433/2268 residues with amino acid changes, including 174 singleton mutations .
• Functional profiling : Eight TRPMPZQ mutants (e.g., p.T1624K) exhibited reduced PZQ sensitivity (EC₅₀ = 1.41 μM vs. 0.74 μM wild-type) in Ca²⁺ flux assays .
• Structural modeling : Mapping mutations to the voltage-sensor-like domain (VSLD) to predict disrupted PZQ binding .

Q. What are the implications of standing genetic variation in schistosome populations for this compound resistance monitoring?

• Transmission genomics : Whole-genome sequencing of 570 S. mansoni samples revealed extensive gene flow across East Africa, facilitating spread of resistance alleles .
• Surveillance strategies : Prioritizing TRPMPZQ genotyping in high-transmission zones and tracking mutations like p.R1843Q (EC₅₀ = 1.11 μM) .
• In vitro–in vivo correlation : Validating laboratory-derived EC₅₀ values with MDA trial outcomes (e.g., cure rates <60% in Senegal vs. >90% in Brazil) .

Methodological Considerations

Q. How should in vitro assays be designed to evaluate this compound's effects on different schistosome life stages?

• Stage-specific dosing : Juvenile worms require 5–10x higher PZQ concentrations (e.g., 10 μM) than adults (1 μM) for equivalent Ca²⁺ influx .
• Time-lapse imaging : Quantifying tegumental damage in real-time using confocal microscopy for cercariae, schistosomula, and adults .
• Drug combination screens : Testing PZQ + artemisinin derivatives in 96-well plates, with viability assessed via ATP-based luminescence .

Q. How do repeated this compound dosing regimens impact treatment outcomes in endemic populations?

• Cure rate optimization : Two-dose regimens improve S. mansoni cure rates from 42–79% (single dose) to 69–91%, but show minimal benefit for S. haematobium .
• Cost-effectiveness analysis : Incremental cost of $153–$211 per QALY gained for double dosing in school-based programs .
• Transmission modeling : Incorporating egg-reduction rates into dynamic models to predict long-term resistance emergence .