Praziquantel

This compound-Induced Calcium Ion Homeostasis Disruption in Parasites

A central tenet of this compound's mechanism is its ability to disrupt calcium ion (Ca2+) homeostasis in susceptible helminths wikipedia.orgnih.govbrighton.ac.ukcambridge.orgpatsnap.comfrontiersin.orgresearchgate.netnih.gov. Experimental evidence indicates that this compound increases the permeability of the parasite's cell membranes to calcium ions, leading to a rapid and uncontrolled influx of Ca2+ into the parasite cells wikipedia.orgbrighton.ac.ukcambridge.orgpatsnap.commims.com. This surge in intracellular calcium concentration is thought to be the primary trigger for the downstream physiological effects observed researchgate.netbrighton.ac.ukpatsnap.com. The calcium-dependent nature of this compound's effects has been demonstrated in studies where the drug's impact on parasite contraction and tegument disruption was inhibited in the absence of extracellular calcium brighton.ac.ukcambridge.org.

Identification and Characterization of Parasite Molecular Targets

Identifying the precise molecular targets of this compound has been a major focus of research wikipedia.orgbrighton.ac.ukcambridge.orgpatsnap.comresearchgate.netnih.govmims.comfishersci.cafishersci.caresearchgate.net. While the exact binding site remains under investigation, several candidate targets have been proposed and studied researchgate.netbrighton.ac.uk.

Transient Receptor Potential Melastatin this compound (TRPMPZQ) Channel as a Primary Candidate Target

Recent research strongly suggests that a transient receptor potential melastatin ion channel, designated TRPMPZQ, is a primary molecular target of this compound in schistosomes and other sensitive flatworms wikipedia.orgnih.govacs.orgbrighton.ac.uknih.govcambridge.orgnih.govmims.comfishersci.cafishersci.caresearchgate.netbiorxiv.org. Studies have shown that this compound activates TRPMPZQ channels, leading to the observed calcium influx nih.govnih.govbiorxiv.orgbiorxiv.org. The activation of this channel by this compound has been demonstrated in heterologous expression systems and native neuronal tissue from schistosomes nih.govfrontiersin.org. The (R)-enantiomer of this compound is significantly more potent in activating Sm.TRPMPZQ compared to the (S)-enantiomer, aligning with their differential anthelmintic activity nih.govbiorxiv.orgbiorxiv.org.

Hypothesized Interactions with Voltage-Gated Calcium Channels

Prior to the identification of TRPMPZQ, voltage-gated calcium channels (Cav channels) were considered primary candidates for this compound's action researchgate.netnih.govbrighton.ac.ukpatsnap.comfrontiersin.orgresearchgate.netfishersci.caresearchgate.net. It was hypothesized that this compound might antagonize or disrupt the function of these channels, leading to uncontrolled calcium influx researchgate.netbrighton.ac.uk. Some studies suggested that this compound might target the β subunits of voltage-gated Ca2+ channels, particularly in Schistosoma mansoni and Schistosoma japonicum drugbank.com. While the direct interaction with classical voltage-gated calcium channels as the sole mechanism has been debated, the disruption of calcium homeostasis mediated by TRPMPZQ activation ultimately impacts calcium-dependent processes regulated by voltage-gated channels and other calcium handling mechanisms brighton.ac.ukcambridge.orgresearchgate.netnih.gov.

Role of Hydrophobic Ligand-Binding Pockets in Target Engagement

Studies investigating the interaction of this compound with its targets, particularly TRPMPZQ, have highlighted the importance of hydrophobic ligand-binding pockets wikipedia.orgnih.govfrontiersin.orgresearchgate.netnih.govresearchgate.netbiorxiv.org. The (R)-praziquantel molecule is thought to engage a hydrophobic binding pocket within the voltage-sensor like domain of the TRPMPZQ channel nih.govnih.govbiorxiv.orgbiorxiv.org. This engagement is crucial for channel activation and subsequent calcium entry nih.govnih.govbiorxiv.org. Mutagenesis studies have identified specific amino acid residues within these hydrophobic pockets that are critical for this compound binding and activity nih.govbiorxiv.org. Differences in these binding pockets, such as a single amino acid change in Fasciola hepatica TRPMPZQ, can explain the differential sensitivity of various parasites to this compound acs.orgnih.govnih.govbiorxiv.orgbiorxiv.org.

Downstream Effects on Parasite Physiology and Morphology

The influx of calcium ions triggered by this compound leads to a cascade of downstream effects on parasite physiology and morphology wikipedia.orgpatsnap.com. The most prominent effects include rapid and sustained muscle contraction, leading to spastic paralysis of the worm wikipedia.orgresearchgate.netbrighton.ac.ukcambridge.orgpatsnap.combiorxiv.orgfrontiersin.org. This paralysis causes the parasite to detach from host tissues wikipedia.orgpatsnap.com.

Adenosine Uptake Systems

Differential Activities Against Trematodes Versus Cestodes

This compound exhibits broad-spectrum activity against most trematodes and cestodes, but there are noted differences in sensitivity between these two classes of flatworms, and even among different species within these classes nih.govpnas.org. While the core mechanism involving calcium influx and tegumental disruption appears to be conserved, variations in the parasite's physiology and molecular targets may contribute to these differential activities brighton.ac.uknih.govnih.govpnas.org.

Research suggests that a transient receptor potential ion channel in the melastatin subfamily (TRPMPZQ) is a candidate target for this compound pnas.orgfrontiersin.org. Studies comparing the activity of this compound analogs against Schistosoma mansoni (a trematode) and cestode models (Echinococcus granulosus and Mesocestoides corti) have shown that structure-activity relationships at their respective TRPMPZQ orthologs are closely mirrored, supporting TRPMPZQ as a relevant therapeutic target nih.gov. Interestingly, cestode TRPMPZQ channels have displayed a higher sensitivity to this compound compared to Schistosoma mansoni TRPMPZQ, which is consistent with the known sensitivity differences between many cestode and schistosome species nih.gov.

However, not all trematodes are equally susceptible. For instance, Fasciola hepatica and Fasciola gigantica (liver flukes) are generally refractory to this compound treatment, potentially due to differences in tegumental structure or other protective mechanisms brighton.ac.uknih.govcore.ac.uk. In contrast, other trematodes like Clonorchis sinensis and Opisthorchis viverrini are susceptible brighton.ac.ukdrugbank.com.

The precise reasons for the differential efficacy are still being investigated, but they likely involve a combination of factors including variations in drug uptake, metabolism, the specific properties of calcium channels or other targets, and the parasite's ability to repair damage or counteract the drug's effects brighton.ac.uknih.govfrontiersin.orgpnas.org.

Reduced Efficacy Against Juvenile Parasite Stages

A significant limitation of this compound is its reduced efficacy against juvenile stages of schistosomes compared to adult worms brighton.ac.uknih.govdrugbank.comfrontiersin.orgresearchgate.netnih.govfrontiersin.orgplos.orgresearchgate.netviamedica.plmdpi.com. While adult worms are highly susceptible, juvenile schistosomes, particularly those around 3-4 weeks post-infection, are largely refractory to the drug, gradually regaining full susceptibility as they mature (6-7 weeks post-infection) brighton.ac.ukdrugbank.com.

Although this compound can still induce calcium influx and muscle contractions in juvenile worms, similar to adults, the juvenile parasites are often able to recover from these effects brighton.ac.ukfrontiersin.orgresearchgate.net. Several hypotheses attempt to explain this reduced efficacy:

Differences in Tegumental Development: The tegument of juvenile worms may be less permeable to the drug or more capable of repairing damage compared to the adult tegument brighton.ac.ukplos.org.

Differential Target Expression or Sensitivity: The expression levels or properties of the molecular targets, such as voltage-gated calcium channels or TRPMPZQ, may differ between juvenile and adult stages, leading to reduced drug binding or response in younger worms brighton.ac.ukdrugbank.comfrontiersin.org.

Enhanced Detoxification or Efflux Mechanisms: Juvenile worms may possess more robust mechanisms for detoxifying or actively pumping the drug out of their cells. Studies have suggested a role for ATP-binding cassette (ABC) transporters in the protection of juvenile worms, as they may express higher levels of these transporters compared to adults frontiersin.orgfrontiersin.orgcore.ac.ukfrontiersin.org.

Transcriptomic Flexibility: Immature worms might exhibit greater flexibility in their gene expression, allowing them to tolerate and survive this compound exposure brighton.ac.uk.

Host Immune Response: The host immune response, which is thought to contribute to the in vivo efficacy of this compound by clearing damaged worms, may be less effective against juvenile stages nih.govfrontiersin.org.

The reduced efficacy against juvenile forms is a major challenge in schistosomiasis control, as these surviving immature worms can mature after treatment and continue to lay eggs, contributing to ongoing transmission frontiersin.orgfrontiersin.orgplos.orgmdpi.com. This highlights the need for potential retreatment or co-administration with drugs effective against juvenile stages frontiersin.orgplos.org.

Data Table: Differential this compound Sensitivity

The Predominant Role of the (R)-Enantiomer in Anthelmintic Activity

Research has consistently demonstrated that the anthelmintic activity of this compound resides predominantly in the (R)-enantiomer, also known as levo-PZQ or (-)-PZQ. nih.govwikipedia.orgplos.orgnih.gov In vitro studies against Schistosoma haematobium adult worms have shown that (R)-PZQ exhibits significantly higher activity compared to the (S)-enantiomer. For instance, (R)-PZQ displayed an IC₅₀ of 0.007 µg/ml at 4 hours, while (S)-PZQ was found to be 501 times less active, with an IC₅₀ of 3.51 µg/ml at the same time point. researchgate.net Similar findings have been reported for Schistosoma mansoni, where (R)-PZQ showed markedly higher activity against newly transformed schistosomula (NTS) with an IC₅₀ of 0.03 µg/ml, while (S)-PZQ had a significantly higher IC₅₀ of 40.0 µg/ml. nih.gov The eudysmic ratio (the ratio of the activity of the more potent enantiomer to the less potent one) calculated against NTS was 1,196, highlighting the substantial difference in activity. nih.gov

In vivo studies in golden Syrian hamsters infected with S. haematobium also support the higher potency of (R)-PZQ. researchgate.net (R)-PZQ resulted in worm burden reductions (WBRs) of 98.5%, 75.6%, and 73.3% at doses of 125.0, 62.5, and 31.0 mg/kg, respectively. researchgate.net While (S)-PZQ did show activity at higher doses (83.0% and 94.1% WBRs at 250.0 and 500.0 mg/kg, respectively), its calculated ED₅₀ was 127.6 mg/kg, compared to 24.7 mg/kg for (R)-PZQ, resulting in a corresponding eudysmic ratio of 5.17 in vivo. researchgate.net

Impact of Enantioselective Metabolism on this compound Efficacy in Biological Systems

This compound undergoes significant first-pass metabolism, primarily in the liver, which can influence the systemic exposure and efficacy of its enantiomers. wikipedia.orgplos.org In humans, this metabolism is enantioselective, largely mediated by the cytochrome CYP450 3A4 isoform. plos.org (R)-PZQ is primarily metabolized to the main monohydroxylated metabolite, R-trans-4-OH-PZQ, which exhibits significantly lower anthelmintic activity compared to the parent (R)-enantiomer. nih.govplos.org The (S)-enantiomer is metabolized into several different monohydroxylated molecules. plos.org

Synthetic Methodologies for this compound and its Derivatives

The synthesis of this compound and its derivatives has been approached through various methodologies, ranging from established multi-step pathways to more convergent multicomponent reactions. nih.govnih.gov The goal of developing new synthetic routes often includes improving efficiency, reducing costs, and minimizing environmental impact compared to earlier methods. google.comtandfonline.comwipo.int

Established Synthetic Pathways (e.g., Reissert Reaction, High-Pressure Catalytic Hydrogenation, Pictet-Spengler Reaction)

One of the initial and still widely used methods for the large-scale production of this compound is the Merck process. mdpi.comnih.gov This route begins with the Reissert reaction of isoquinoline. mdpi.comnih.govasianpubs.org The Reissert reaction, however, is limited in the variety of acid chlorides it can utilize and involves the use of toxic cyanide, posing environmental challenges. mdpi.comnih.govasianpubs.org Following the Reissert reaction, a key step in the Merck process involves high-pressure catalytic hydrogenation (around 70 atm) to generate a 1-aminomethyltetrahydroisoquinoline intermediate. mdpi.comnih.govresearchgate.net Subsequent acylation and cyclization steps complete the synthesis. mdpi.comnih.gov

The Pictet-Spengler reaction has also been explored for the synthesis of this compound and its derivatives, particularly for the construction of the tetrahydroisoquinoline core. mdpi.comresearchgate.netblogspot.comthieme-connect.com This reaction involves the cyclization of a β-arylethylamine with a carbonyl compound. blogspot.com While the Pictet-Spengler reaction can be used in the synthesis of the this compound scaffold, achieving high enantioselectivity in catalytic asymmetric versions of this reaction for PZQ synthesis has been a subject of research. blogspot.comresearchgate.net Solid-phase synthesis utilizing the Pictet-Spengler reaction has also been demonstrated as an efficient route. thieme-connect.com

Multicomponent Reactions for Scaffold Diversification (e.g., Ugi Four-Component Reaction)

Multicomponent reactions (MCRs) offer a powerful approach for the convergent and efficient synthesis of complex molecules, including this compound derivatives, allowing for rapid scaffold diversification. mdpi.comnih.govresearchgate.netacsgcipr.orgsci-hub.secapes.gov.brresearchgate.netmdpi.com The Ugi four-component reaction (U-4CR) is a prominent example of an MCR that has been successfully applied in the synthesis of this compound intermediates and analogues. mdpi.comnih.govnih.govresearchgate.netacsgcipr.orgsci-hub.secapes.gov.brresearchgate.netmdpi.comcapes.gov.brorgsyn.orgrsc.org

The Ugi reaction typically involves the reaction of an amine, a carbonyl compound (aldehyde or ketone), an isocyanide, and a carboxylic acid to form α-aminoacyl amides. mdpi.comorgsyn.orgrsc.org In the context of this compound synthesis, a highly efficient two-step, one-pot procedure has been developed that combines a four-component Ugi reaction followed by a Pictet-Spengler reaction. mdpi.comnih.govnih.govresearchgate.netacsgcipr.orgcapes.gov.brresearchgate.net This approach offers significant advantages in terms of structural diversity due to the wide availability of commercially accessible carboxylic acids and aldehydes that can be incorporated into the Ugi reaction. mdpi.comnih.gov The Ugi-Pictet-Spengler sequence allows for the convergent assembly of the this compound core and the introduction of various substituents, facilitating the exploration of the structure-activity relationship. nih.gov This methodology has enabled the synthesis of novel this compound derivatives with structural variations that are otherwise difficult to access through traditional linear synthesis. nih.gov

Continuous Flow Chemistry Approaches for Optimized Production

Continuous flow chemistry offers potential advantages over traditional batch synthesis for the production of pharmaceuticals, including improved process control, safety, and reduced reaction times. researchgate.netmdpi.com Research has explored the application of continuous flow methods for the synthesis of this compound, aiming to develop more economical and efficient routes. researchgate.netthieme-connect.dethieme-connect.com One study described a precise and reliable flow chemistry method starting from phenylethylamine, achieving the continuous preparation of this compound in significantly less time (approximately 3–4 hours) compared to conventional methods (approximately 3–4 days). researchgate.netthieme-connect.com This approach also demonstrated a reduced requirement for key intermediates. researchgate.net The use of integrated flow reactors and the ability to maintain intermediates in solution throughout the process are key aspects of these optimized flow synthesis methods. thieme-connect.de

Chiral Auxiliary Mediated Asymmetric Synthesis of Enantiomers

This compound is administered as a racemic mixture, but the (R)-enantiomer is primarily responsible for its anthelmintic activity. mdpi.comresearchgate.net Asymmetric synthesis methods are employed to obtain enantiomerically pure compounds. sigmaaldrich.comyork.ac.uktcichemicals.com Chiral auxiliary mediated asymmetric synthesis involves temporarily attaching a chiral molecule (the auxiliary) to the substrate to control the stereochemical outcome of a reaction. sigmaaldrich.comyork.ac.uk After the desired stereochemistry is established, the auxiliary is removed, ideally for recycling. sigmaaldrich.comyork.ac.uk While the provided text specifically mentions chiral auxiliary mediated synthesis in the context of existing routes for (R)-praziquantel, it notes that some methods using chiral auxiliaries in equimolar amounts might not be practically feasible in certain research contexts. researchgate.net Other asymmetric synthesis approaches, such as asymmetric transfer hydrogenation, have also been explored for the enantioselective synthesis of (R)-praziquantel. researchgate.net

Structure-Activity Relationship (SAR) Studies of this compound Derivatives

Extensive SAR studies have been conducted to understand how modifications to the this compound structure affect its activity against parasitic flatworms and their TRPMPZQ orthologs. nih.govnih.govnih.govresearchgate.net These studies aim to identify derivatives with enhanced potency, broader spectrum activity (including against juvenile parasites), and the ability to overcome potential drug resistance. grantome.comnih.govmdpi.comnih.gov The pyrazinoisoquinoline scaffold of this compound is a critical element for its activity. nih.govresearchgate.net

Correlating Analog Activity with TRPMPZQ Orthologs Across Parasite Species

Recent research has focused on correlating the activity of this compound analogs against different parasite species with their activity at the respective TRPMPZQ orthologs found in those species. nih.govnih.govthieme-connect.detandfonline.com These studies have shown a good alignment between the SAR of this compound derivatives in causing worm paralysis and their pharmacological profile at TRPMPZQ in vitro. nih.govnih.gov The SAR of TRPMPZQ can differ between parasite species, which may explain why certain this compound derivatives show varying activity against different parasites (e.g., some are more active against cestodes than schistosomes). nih.govresearchgate.net Differences in the amino acid residues lining the TRPMPZQ ligand binding pocket are thought to contribute to these species-specific differences in sensitivity. nih.gov

Systematic Modification of the Pyrazinoisoquinoline Scaffold for Enhanced Potency

Modifications to the pyrazinoisoquinoline scaffold of this compound have been systematically investigated to enhance potency. nih.govresearchgate.netnih.gov While major modifications to the core structure are often poorly tolerated, certain alterations can preserve or even improve activity. biorxiv.org For example, a fluorinated scaffold or an enlarged piperidine ring have been explored. biorxiv.org Studies involving the modification of the aromatic ring of the tetrahydroisoquinoline moiety have shown that substitutions can affect activity. mdpi.com The amide bond at position 2 of the pyrazinoisoquinoline scaffold appears essential for activity against Schistosoma japonicum. nih.gov

Exploration of Novel Chemical Spaces and Hybrid Compounds for Anthelmintic Activity

Beyond direct modifications of the this compound scaffold, researchers are exploring novel chemical spaces and developing hybrid compounds to identify new anthelmintic agents. researchgate.netnih.gov This involves combining the this compound structure with other pharmacophores or exploring entirely new chemical entities with potential activity against parasitic flatworms. mdpi.comnih.govresearchgate.net The strategy of molecular hybridization, such as coupling the this compound tetrahydroisoquinoline scaffold with other moieties like cinnamic acids, has shown promising results in generating compounds with potent activity. mdpi.com Exploring novel chemical spaces and structural diversity, particularly in the context of target-based screening approaches utilizing TRPMPZQ, is seen as crucial for developing alternatives to this compound. researchgate.net

Investigation of Specific Functional Group Derivatizations (e.g., Sulfonamides, Dithiocarbamates)

Specific functional group derivatizations of this compound have been investigated to explore their impact on anthelmintic activity and potential new mechanisms of action. nih.govnih.govnist.gov

Sulfonamides: this compound derivatives bearing a primary sulfonamide group have been proposed as hybrid drugs, potentially targeting carbonic anhydrase enzymes in parasites like Schistosoma mansoni (SmCA) in addition to the effects related to the this compound moiety. nih.govtandfonline.comresearchgate.nettandfonline.com SAR studies on these sulfonamide derivatives have indicated that the linker between the pyrazinoisoquinolinone moiety and the benzenesulfonamide group plays a significant role in modulating potency and selectivity against different carbonic anhydrase isoforms. nih.govtandfonline.com

Dithiocarbamates: The substance class of dithiocarbamates, some derived from the structure of disulfiram, has shown promising in vitro antischistosomal activities. nih.govresearchgate.netresearchgate.netnih.gov Detailed SAR studies on dithiocarbamate derivatives have been conducted, exploring modifications on both sides of the dithiocarbamate core. researchgate.netnih.gov These studies have identified derivatives with activity in the low micromolar range against Schistosoma mansoni, affecting parasite motility, egg production, and tegument integrity. nih.govresearchgate.netnih.gov While not direct this compound derivatives in all cases, the exploration of dithiocarbamates represents an investigation into novel chemical spaces with anthelmintic potential. researchgate.netnih.gov Some dithiocarbamates have also shown activity against Echinococcus multilocularis. researchgate.net

Absorption and Distribution Studies in Animal Models

This compound is generally well absorbed from the gastrointestinal tract in almost all species studied. msdvetmanual.commerckvetmanual.com However, its systemic bioavailability is often relatively low due to extensive first-pass metabolism in the liver. wikipedia.orgmsdvetmanual.comoup.comdrugbank.com

Studies in sheep have shown that intramuscular administration of this compound resulted in significantly higher maximum concentration (Cmax) and area under the concentration-time curve (AUC) values compared to oral treatment, even at a higher oral dose. msdvetmanual.com This suggests that the route of administration can significantly impact systemic exposure. In dogs, absorption after oral administration is higher when the drug is given with food. merckvetmanual.com

Following absorption, this compound is distributed to various organs. merckvetmanual.comoup.com In non-clinical studies, it has been found to concentrate particularly in the liver and kidneys. oup.com Higher concentrations than those in plasma have been observed in the lung, pancreas, adrenal glands, pituitary, and salivary gland. oup.com this compound is also known to cross the blood-brain barrier, which explains its efficacy in treating neurocysticercosis. asm.orgoup.com

Stereoselective Metabolism and Metabolite Identification in Model Systems (e.g., Hydroxylation Products, Cytochrome P450 Enzymes)

This compound is administered as a racemic mixture containing equal proportions of the R-(-)- and S-(+)-enantiomers. oup.comnih.gov The drug undergoes rapid and extensive metabolism, primarily in the liver, mediated largely by cytochrome P450 (CYP) enzymes. wikipedia.orgasm.orgnih.govdrugbank.comnih.govnih.gov CYP3A4, CYP3A5, CYP2C19, and CYP2C9 are among the key enzymes involved in this compound metabolism. nih.govnih.govfrontiersin.org

Metabolism leads to the formation of numerous metabolites, predominantly monohydroxylated and dihydroxylated derivatives. nih.gov The main metabolite identified is R-trans-4-OH-praziquantel. asm.orgfrontiersin.org Studies using ultra-performance liquid chromatography coupled with mass spectrometry have identified many phase I and new phase II metabolites in animal samples, indicating that oxidation, dehydrogenation, and glucuronidation are major metabolic reactions. nih.gov

Metabolism of this compound is stereoselective, with observed differences in the formation of metabolites between the R- and S-enantiomers. nih.govnih.gov In vitro studies with recombinant enzymes have shown that CYP2C9 and CYP3A4 exhibit different catalytic activity towards the this compound enantiomers. nih.gov Competitive inhibition between the this compound enantiomers for binding to CYP2C9, CYP2C19, CYP3A4, and CYP3A5 has also been revealed. nih.gov

Influence of Host Physiologic Factors on this compound Pharmacokinetics in Preclinical Studies

Host physiologic factors can significantly influence the pharmacokinetics of this compound in preclinical studies. Factors such as the health of the liver, diet, and potential drug-drug interactions can affect systemic drug levels and, consequently, efficacy. asm.orgnih.govasm.orgfrontiersin.org

Studies in mice have demonstrated that a protein-deficient diet can reduce the efficacy of this compound against Schistosoma mansoni infection. biorxiv.org This reduced efficacy was associated with higher worm and liver egg burdens compared to mice on a standard diet. biorxiv.org

The involvement of the cytochrome P448 system in the first-pass metabolism of this compound is a significant host factor contributing to variability in drug exposure. asm.org The use of a pan-CYP inhibitor, 1-aminobenzotriazole (ABT), in the Schistosoma mansoni mouse model increased R-praziquantel plasma exposures significantly, although this did not directly predict efficacy. nih.govmmv.org Conversely, pre-treatment with a CYP inducer like dexamethasone decreased systemic plasma exposure of R-praziquantel but maintained efficacy. plos.orgnih.govmmv.org This suggests that high concentrations of R-praziquantel in the portal vein before extensive hepatic first-pass metabolism are critical for efficacy against S. mansoni adult worms residing in the mesenteric veins. plos.orgnih.gov

Co-administration of other drugs can also influence this compound pharmacokinetics. For example, cimetidine, a CYP inhibitor, has been shown to increase this compound plasma concentrations in studies. asm.org

In Vitro Pharmacodynamic Assessments (e.g., Worm Motility, Egg Production, Tegumental Damage Assays)

In vitro studies have been instrumental in characterizing the direct effects of this compound on parasitic worms. Within seconds of exposure, adult schistosomes exhibit rapid and sustained contraction of their musculature. This effect is believed to be linked to the disruption of calcium ion homeostasis, leading to an influx of calcium ions into the parasite. patsnap.combrighton.ac.ukdrugbank.commims.com

This compound also causes significant damage to the parasite's tegument, the outer surface. patsnap.comresearchgate.net This tegumental damage can include vacuolization and disruption, compromising the structural integrity of the worm and potentially exposing parasite antigens to the host immune system. patsnap.com Studies on Mesocestoides corti, a cestode model, have also demonstrated extensive tissue damage, particularly to the tegument, with adult forms being more susceptible to this compound exposure in vitro.

In vitro assessments often include evaluating changes in worm motility and egg production. This compound has been shown to reduce worm motility significantly. cambridge.org Studies have also assessed the impact on egg production as an indicator of parasite viability and reproductive capacity. plos.org

The R-enantiomer of this compound is considered primarily responsible for the antischistosomal activity observed in vitro. acs.org While the S-enantiomer may induce transient hyperactivity, the R-enantiomer causes spastic paralysis and rapid tegumental damage. acs.org Metabolites like S-trans- and S-cis-4'-hydroxythis compound have shown little to no activity in vitro. acs.org

Efficacy Studies in Defined Animal Infection Models (e.g., Schistosoma mansoni Mouse Model)

Defined animal infection models, particularly the Schistosoma mansoni mouse model, are widely used to evaluate the in vivo efficacy of this compound. wikipedia.orgplos.orgnih.govmmv.orgcambridge.orgplos.orgacs.orgasm.orgmdpi.comfrontiersin.org These models allow for the assessment of worm burden reduction, egg load in tissues, and the impact on parasite development and pathology.

Studies in the S. mansoni mouse model have consistently shown that this compound treatment leads to a significant reduction in worm burden and egg counts in the liver and intestine. biorxiv.orgplos.orgmdpi.com The efficacy can vary depending on the treatment regimen and the stage of infection. For example, while highly effective against adult worms, this compound shows limited efficacy against immature schistosomes. plos.orgmdpi.com

Research in the mouse model has also explored factors influencing efficacy, such as host nutritional status and the use of combination therapies. As mentioned earlier, protein deficiency in mice reduced this compound efficacy. biorxiv.org Studies combining this compound with other compounds, such as amiodarone or kinase inhibitors, have been investigated in the mouse model to explore potential synergistic effects and improve efficacy, particularly against prepatent infections or in cases of reduced susceptibility. cambridge.orgasm.org

The S. mansoni mouse model has also been used to study the development of reduced susceptibility to this compound. Laboratory studies have successfully induced this compound resistance in schistosomes in mice through successive subcurative doses or increasing drug pressure over generations. frontiersin.org Isolates from treated mice showing reduced sensitivity in vivo also exhibited decreased muscle contraction, tegumental disruption, and calcium influx in vitro. frontiersin.org

Data from efficacy studies in the S. mansoni mouse model often involve quantifying worm burden reduction and egg reduction rates in different organs.

Table 1: Example Data from Schistosoma mansoni Mouse Model Efficacy Studies

The S. mansoni mouse model remains a critical tool for evaluating the in vivo efficacy of this compound and potential new drug candidates or treatment strategies against schistosomiasis. plos.orgnih.gov

Establishing Pharmacokinetic-Pharmacodynamic Relationships in Experimental Infection Models

Research into the pharmacokinetic-pharmacodynamic (PK/PD) relationships of this compound in experimental infection models has primarily utilized the Schistosoma mansoni mouse model to understand the factors driving its efficacy against adult schistosomes residing in the mesenteric veins. These studies aim to correlate drug exposure with antiparasitic outcomes, such as worm burden reduction (WBR).

Experimental investigations in the S. mansoni mouse model have revealed that systemic plasma exposure to this compound, particularly the active (R)-enantiomer, does not consistently predict efficacy. nih.govacs.orgplos.orgresearchgate.net This observation suggests that systemic circulation levels may not fully reflect the drug concentrations at the site of action. Instead, estimated concentrations in the portal vein and mesenteric veins, where the adult worms are located, appear to be more relevant predictors of antiparasitic activity. nih.govacs.orgplos.orgresearchgate.net

Studies have explored the impact of modulating drug metabolism on the PK/PD relationship. For instance, pre-treatment of mice with 1-aminobenzotriazole (ABT), a pan-cytochrome P450 (CYP) inhibitor, led to significant increases in systemic plasma exposure of (R)-praziquantel, ranging from approximately 10 to 20-fold. nih.govplos.orgresearchgate.net However, these substantial increases in systemic exposure did not result in a proportional enhancement of efficacy, as measured by WBR. nih.govplos.orgresearchgate.net Conversely, pre-treatment with dexamethasone, a CYP inducer, caused a decrease in systemic plasma exposure of (R)-praziquantel by approximately 10-fold while maintaining the drug's efficacy. nih.govplos.orgresearchgate.netnih.gov These findings support the hypothesis that high local concentrations of this compound available before extensive hepatic first-pass metabolism are critical for efficacy against S. mansoni adult worms in the mesenteric veins. nih.govplos.orgresearchgate.net

Quantitative analyses in the S. mansoni mouse model have provided insights into the exposure levels associated with efficacy. Without metabolic modifiers, a higher dose of this compound resulted in increased systemic exposure and greater WBR. For example, in one study, a 200 mg/kg dose yielded a 68% WBR with specific plasma (R)-PZQ Cmax and AUC values, while a 400 mg/kg dose achieved a 97% WBR with correspondingly higher exposure parameters. nih.govresearchgate.net

The data below illustrate the relationship between systemic (R)-PZQ exposure and worm burden reduction in the S. mansoni mouse model under different conditions:

Note: Specific Cmax and AUC values for the 400 mg/kg dose without ABT, and for treatments with ABT p.o. or DEX pre-treatment where not explicitly stated as numerical values in the snippets, are indicated by '-'. The effect of DEX is described qualitatively in terms of fold change and efficacy maintenance.

Based on extrapolation from systemic exposures, it was estimated that a free exposure of approximately 20 µM*h of (R)-praziquantel in the portal vein was necessary to achieve a worm burden reduction exceeding 60% in the S. mansoni mouse model. nih.govplos.orgresearchgate.net This finding underscores the importance of achieving adequate drug exposure at the specific anatomical location of the parasite.

While the majority of detailed PK/PD studies in experimental models focus on Schistosoma species, particularly S. mansoni in mice, this compound is also effective against certain cestode infections. nih.gov However, the specific PK/PD relationships in experimental models for cestode infections are less extensively documented in the provided search results compared to those for schistosomiasis.

The studies in experimental models highlight the complex interplay between this compound's pharmacokinetics and its pharmacodynamic effects, emphasizing the significance of local drug concentrations at the site of infection rather than solely relying on systemic exposure metrics for predicting efficacy in certain parasitic infections like schistosomiasis.

Laboratory-Induced this compound Resistance in Schistosome Strains

Laboratory studies have successfully demonstrated the ability to induce PZQ resistance in schistosomes, particularly Schistosoma mansoni. frontiersin.orgliberty.edunih.govriojournal.comfrontiersin.orgtandfonline.com This is often achieved through the repeated exposure of parasite populations to increasing or subcurative doses of PZQ, typically in experimental rodent or snail hosts. liberty.edunih.govfrontiersin.orgtandfonline.comcore.ac.uk

For instance, one study in 1994 subjected a population of S. mansoni-infected mice to increasing PZQ drug pressure. By the seventh generation, 93% of the resistant schistosomes survived three PZQ doses of 300 mg/kg, a dose that killed 89% of the control group. liberty.edunih.govfrontiersin.org Another study demonstrated that resistance to the therapeutic dose of PZQ could be induced in subsequent generations of S. mansoni in mice through successive subcurative doses. liberty.edunih.govfrontiersin.orgtandfonline.com Resistance induction has also been achieved in different life stages of S. japonicum. nih.govfrontiersin.org These laboratory experiments provide strong evidence that schistosomes possess the capacity to develop resistance under drug pressure. nih.govfrontiersin.orgcore.ac.uk

Field Reports and Epidemiological Observations of Reduced this compound Efficacy

Alongside laboratory findings, several field reports and epidemiological observations have suggested reduced efficacy of PZQ in specific endemic areas following continuous drug exposure. frontiersin.orgliberty.edunih.govriojournal.comfrontiersin.org These reports often highlight low cure rates (CR) despite treatment. frontiersin.orgriojournal.com

Early reports of apparent S. mansoni field resistance emerged from areas like Senegal and the Nile Delta region of Egypt. nih.govriojournal.comfrontiersin.org Studies in Senegal observed low cure rates, although factors other than drug resistance, such as pre-treatment intensity or age, were also considered as potential explanations. riojournal.com Reduced sensitivity to PZQ has also been reported in Kenya and Uganda. nih.gov

However, interpreting field observations is complex, as factors other than true drug resistance can influence treatment outcomes, including rapid re-infection, inadequate dosing, high levels of juvenile worms (which are less susceptible to PZQ), and high worm burdens. frontiersin.orgriojournal.comfrontiersin.orgbiomedcentral.combiorxiv.org Some reviews and meta-analyses suggest that while reduced efficacy is observed, there is currently no consistent evidence for widespread, clinically relevant PZQ resistance in field populations, and low cure rates may often be attributable to these confounding factors. frontiersin.orgnih.govriojournal.comfrontiersin.orgbiomedcentral.com Nevertheless, the persistent reports and the potential for selection pressure from MDA programs underscore the need for continued surveillance and research. frontiersin.orgriojournal.combiomedcentral.com

Altered Drug Metabolism and Enhanced Detoxification Pathways in Parasites

One proposed mechanism of PZQ resistance involves altered drug metabolism and enhanced detoxification pathways within the parasite. frontiersin.orgliberty.educore.ac.uk It has been suggested that resistant worms may be better able to metabolize PZQ into less active or inactive compounds compared to sensitive worms. liberty.edufrontiersin.org

Studies have investigated the role of enzymes potentially involved in detoxification. While glutathione S-transferase (GST) isoenzymes were once suggested as a potential receptor or target for PZQ, evidence has largely contradicted this hypothesis. However, the broader concept of enhanced metabolic breakdown of the drug by parasite enzymes remains a plausible mechanism. core.ac.uk

Genetic Variation and Single Nucleotide Polymorphisms (SNPs) in Target Genes (e.g., Sm.TRPMPZQ Channel)

Recent research has significantly advanced the understanding of potential genetic determinants of PZQ resistance, particularly focusing on the parasite's drug target. The transient receptor potential melastatin (TRPM) ion channel, specifically Sm.TRPMPZQ in S. mansoni, has been identified as a key molecular target of PZQ. frontiersin.orgliberty.edufrontiersin.orgbiomedcentral.combiorxiv.orgnih.govplos.orgbiorxiv.orgnih.gov PZQ is thought to activate this channel, leading to calcium influx and subsequent paralysis of the worm. liberty.edufrontiersin.orgbiomedcentral.com

Genetic variation, including Single Nucleotide Polymorphisms (SNPs), within or near the Sm.TRPMPZQ gene has been strongly implicated in conferring reduced susceptibility to PZQ. frontiersin.orgliberty.edufrontiersin.orgbiomedcentral.combiorxiv.orgnih.govplos.orgbiorxiv.orgnih.gov Genome-wide association studies (GWAS) have identified regions in the schistosome genome, including the locus containing Sm.TRPMPZQ, that are associated with PZQ responsiveness. biomedcentral.combiorxiv.orgnih.govnih.gov

Studies using marker-assisted selection based on a single SNP in the Sm.TRPMPZQ gene have generated schistosome populations with vastly different PZQ sensitivities, showing over a 377-fold difference in responsiveness. nih.govplos.orgnih.gov Resistant parasites have been shown to exhibit lower expression levels of Sm.TRPMPZQ compared to sensitive parasites. biorxiv.orgnih.govplos.orgnih.gov Furthermore, mutations within the predicted PZQ binding site of TRPMPZQ have been shown to result in loss of sensitivity to the drug. biorxiv.org Analysis of field isolates has also revealed a high degree of variability within the Sm.TRPMPZQ gene, including mutations that could potentially impact drug binding or channel function. biorxiv.org

Role of Drug Efflux Mechanisms (e.g., ABC Transporters)

Drug efflux mechanisms, particularly those mediated by ATP-binding cassette (ABC) transporters, are another proposed mechanism contributing to PZQ resistance in schistosomes. frontiersin.orgplos.orgplos.orgcore.ac.ukcambridge.orgnih.gov ABC transporters are a family of proteins that actively pump a wide variety of substrates, including toxins and drugs, out of cells. frontiersin.orgplos.orgplos.orgcambridge.orgnih.gov They are well-known for their role in multidrug resistance in various organisms, including other parasites. frontiersin.orgplos.orgplos.orgcambridge.orgnih.gov

Schistosomes possess a number of ABC transporter genes in their genome. frontiersin.orgcambridge.org It is hypothesized that increased expression or activity of these transporters could lead to enhanced efflux of PZQ from parasite cells, thereby reducing the effective intracellular concentration of the drug and conferring resistance. frontiersin.orgplos.orgplos.org

Whole-Genome Sequencing to Identify Resistance-Associated Loci

Whole-genome sequencing (WGS) is a powerful tool used to identify genetic variations across the entire genome of resistant and susceptible parasite populations. By comparing the genomes of parasites with differing responses to this compound, researchers can identify loci (specific positions on a chromosome) that are statistically associated with resistance. Studies utilizing WGS have investigated genetic variation in globally dispersed populations of Schistosoma mansoni. nih.gov This approach has characterized variation across the transient receptor potential melastatin ion channel (TRPMPZQ), which has been identified as a target of this compound and influences susceptibility. nih.gov WGS analysis of S. mansoni samples from various countries has revealed broad-scale genetic structure and extensive transmission. nih.gov Furthermore, WGS of parasite populations from individuals before and after this compound treatment has been used to quantify the immediate genetic impact of the drug. nih.gov While some studies using WGS have found that genomic diversity remained varied and unstructured despite long-term this compound use, suggesting that low efficacy in certain instances might be due to factors other than resistance, the approach remains valuable for identifying potential genetic determinants. frontiersin.orgnih.govliberty.edu

Genome-Wide Association Studies (GWAS) for this compound Resistance Phenotypes

Genome-Wide Association Studies (GWAS) are employed to identify genetic variants associated with specific traits or phenotypes, such as this compound resistance. This involves examining the genomes of a large number of individuals (or parasite samples) and looking for correlations between genetic markers (like Single Nucleotide Polymorphisms or SNPs) and the resistance phenotype. GWAS has been used to determine if specific genetic regions in S. mansoni are significantly different between pools of this compound-resistant and sensitive worms. biomedcentral.com One study using GWAS identified a transient receptor potential (TRPM) channel, SmTRPMPZQ, as significantly associated with extreme this compound resistance in S. mansoni. biomedcentral.combiorxiv.orgnih.gov This research indicated that the resistant phenotype showed recessive inheritance, with homozygotes carrying specific alleles surviving this compound treatment. biomedcentral.com Reanalysis of GWAS data using updated genome assemblies has further refined the understanding of resistance loci, suggesting that a single locus on chromosome 3, rather than two independent loci, might determine drug response, indicating a potentially monogenic basis for resistance in some cases. asm.orgresearchgate.net

Investigations into the Role of Parasite Genetic Diversity and Population Dynamics in Resistance Development

The genetic diversity within parasite populations and their dynamic changes under drug pressure are critical factors influencing the potential for resistance development. High genetic diversity within a parasite population can provide a larger pool of genetic variations, increasing the likelihood that some individuals may possess pre-existing alleles that confer reduced susceptibility to the drug. frontiersin.orgdovepress.com Mass drug administration (MDA) programs, while successful in reducing prevalence and intensity of infections, can exert significant selective pressure on parasite populations. frontiersin.org This pressure could theoretically lead to the selection and increase in frequency of resistant alleles. frontiersin.orgdovepress.com Conversely, a reduction in genetic diversity following treatment might suggest a lower likelihood of the population adapting to drug pressure. frontiersin.org Studies have investigated the genetic consequences of MDA and drug pressure using genotyping technologies and molecular markers associated with this compound resistance. liberty.edu While some genomic studies have found no long-term decrease in the genetic diversity of S. mansoni worms even after MDA, the impact of selection on genetic structure and the potential for resistance evolution remain active areas of research. nih.govnih.govliberty.edu The high rates of gene flow and diversity in S. mansoni populations could potentially prevent the fixation of resistance alleles by diluting them with susceptible alleles from untreated populations. frontiersin.org However, the scale-up of MDA programs may heighten drug selection pressures, increasing the risk of resistant schistosomes emerging. frontiersin.org

Genomics and Transcriptomics for Target and Resistance Gene Discovery

Genomics and transcriptomics play a crucial role in identifying genes associated with this compound targets and potential resistance mechanisms in schistosomes. Whole-genome data from parasite populations under drug selection pressure can provide insights into the genetic basis of reduced susceptibility to this compound. plos.org Studies have utilized transcriptomic analysis to examine differential gene regulation in laboratory strains of Schistosoma mansoni with diminished susceptibility to PZQ. nih.gov While transcriptomic analysis can reveal differentially regulated genes, it may not immediately identify mutations in a target gene that cause loss of function without altered expression. nih.gov

Research has implicated a transient receptor potential melastatin (TRPM) ion channel, designated Sm.TRPMPZQ in S. mansoni, as a likely target for PZQ action. frontiersin.orgbiorxiv.org Genomic and transcriptomic resources have revealed the presence of TRPMPZQ orthologs in the genomes of various flatworms sensitive to PZQ. plos.org Genetic analysis of PZQ-resistant S. mansoni laboratory strains has identified this TRPM channel as being responsible for variation in PZQ response. biorxiv.org Potential PZQ resistance may arise from genetic mutations in SmTRPMPZQ that reduce its activity. frontiersin.org Mutagenesis studies have shown that mutations within the PZQ binding pocket of SmTRPMPZQ can decrease sensitivity, sometimes leading to a complete loss of PZQ activity. frontiersin.org However, whole-genome sequencing of S. mansoni from a Ugandan hotspot did not find evidence of genomic selection acting on SmTRPMPZQ, suggesting the complexity of resistance mechanisms in the field. frontiersin.org Other candidate genes, such as the S. mansoni P-glycoprotein (smdr2), which shows increased protein expression after exposure to sub-lethal PZQ doses, have also been proposed in the context of resistance. plos.org

Proteomics and Immunomics for Antigen Discovery and Drug-Induced Vaccination (DIV) Phenomena

Proteomics and immunomics contribute to the identification of parasite antigens and the understanding of the Drug-Induced Vaccination (DIV) phenomenon associated with this compound treatment. This compound treatment damages the parasite's tegument, releasing surface antigens that can elicit an immune response in the host, potentially leading to immunologic resistance to reinfection – the DIV phenomenon. researchgate.netfrontiersin.orgescholarship.org

Immunomics-guided antigen discovery has been employed to identify the antigenic targets of DIV antibodies in human schistosomiasis. researchgate.netfrontiersin.orgnih.gov By screening recombinant proteome arrays with sera from individuals treated with this compound who were either reinfected or resistant to reinfection, researchers have identified numerous antigens that are targets of DIV antibodies. researchgate.netfrontiersin.orgnih.gov IgG responses to these antigens were significantly elevated in individuals resistant to reinfection compared to those who were reinfected. researchgate.netnih.gov A cystatin cysteine protease inhibitor, for instance, was identified as a unique target of DIV IgG. researchgate.net These identified antigens hold promise as subunit vaccine targets for a drug-linked vaccination approach to schistosomiasis control. researchgate.netescholarship.org

Crystallographic Studies of Parasite Target Proteins in Complex with this compound or Analogues

X-ray crystallography is a key technique used to determine the three-dimensional structures of parasite proteins, including potential this compound targets, and their complexes with this compound or its analogues. This provides direct visualization of how the drug binds to the protein, revealing the specific residues involved in the interaction and the conformational changes that may occur upon binding.

Crystal structures of glutathione S-transferase (GST) from Schistosoma japonicum (SjGST) have been determined both in its unligated form and in complex with this compound. researchgate.netnih.gov These studies showed that this compound binds to SjGST in the dimer interface groove adjoining the two catalytic sites, with one drug molecule binding per enzyme homodimer at therapeutic concentrations. researchgate.netnih.gov This interaction implicates this compound in the steric inhibition of SjGST catalytic and transport functions for large ligands. researchgate.netnih.gov Differences in the xenobiotic binding region between parasitic and mammalian GSTs, along with the identified PZQ binding site, can inform the design of novel antischistosomal drugs. researchgate.netnih.gov Crystallographic determination of other potential parasite drug targets in complex with inhibitors is also underway. iucr.org

Molecular Modeling and Docking Simulations for Ligand-Protein Binding Characterization

Molecular modeling and docking simulations are computational techniques used to predict and characterize the binding interactions between this compound or potential drug candidates and target proteins. researchgate.netplos.orgtandfonline.commdpi.comsemanticscholar.org These methods can estimate binding affinities, identify potential binding sites, and analyze the types of interactions (e.g., hydrogen bonds, hydrophobic interactions) that stabilize the protein-ligand complex. plos.org

Molecular docking studies can be used to screen large libraries of compounds to identify potential inhibitors based on their predicted binding affinity to a target protein. mdpi.com Following docking, molecular dynamics simulations are often employed to assess the stability of the protein-ligand complexes over time, providing a more dynamic view of the interaction under simulated physiological conditions. plos.orgtandfonline.commdpi.comsemanticscholar.org These simulations can validate the stability of the designed compounds within the binding site and provide insights into the flexibility of the protein-ligand complex. plos.orgmdpi.com For example, molecular docking and dynamics simulations have been used in the search for novel inhibitors of Schistosoma mansoni Dihydroorotate dehydrogenase (SmDHODH) and Thioredoxin glutathione reductase (SmTGR), both considered promising therapeutic targets. plos.orgtandfonline.commdpi.com Computational modeling has also been used to evaluate the docking pose of this compound within the binding site of the human serotoninergic 5-HT2B receptor, identifying critical residues for PZQ-mediated agonist activity. nih.gov

Virtual Screening Strategies for Identification of Novel Anthelmintic Chemotypes

Virtual screening (VS) is a computational technique used to search large libraries of chemical compounds for potential drug candidates. This approach is increasingly being applied in the search for new anthelmintics, including those with novel chemotypes that could be effective against this compound-resistant parasites or target different life stages. researchgate.netnih.gov

Studies have employed structure-based virtual screening (SBVS) targeting specific parasite proteins, such as Schistosoma mansoni thioredoxin glutathione reductase (SmTGR), an essential enzyme for parasite survival. nih.govresearchgate.net By screening databases of approved drugs or novel compounds against the known or modeled structures of these targets, researchers aim to identify molecules that are predicted to bind to and inhibit the target protein. nih.govresearchgate.netnih.gov

One study utilized QSAR (Quantitative Structure-Activity Relationship)-based virtual screening of SmTGR inhibitors integrated with high content screening (HCS) to identify new antischistosomal agents. nih.gov This approach successfully identified compounds with novel chemical scaffolds active against both schistosomula and adult worms at low micromolar concentrations, highlighting their potential as promising hits for further optimization. nih.gov Another structure-based virtual screening approach targeted the sodium-bile acid co-transporter of Clonorchis sinensis (CsSBAT), identifying potential inhibitor candidates to overcome this compound resistance in liver flukes. nih.gov

Predictive Modeling of this compound Activity and Resistance

Predictive modeling approaches are being developed to better understand and forecast this compound activity and the potential for resistance. These models can incorporate various factors, including drug pharmacokinetics, host immune status, and parasite genetics. researchgate.netnih.govplos.org

Research into the pharmacokinetic-pharmacodynamic (PK-PD) relationship of this compound in animal models, such as the Schistosoma mansoni-infected mouse model, aims to determine the key factors influencing its efficacy. plos.orgmmv.org Studies have investigated the plasma exposure levels of the active enantiomer, (R)-PZQ, and their correlation with worm burden reduction. plos.orgmmv.org These models can help predict optimal dosing regimens and identify factors that may lead to suboptimal drug exposure and potentially contribute to reduced efficacy or the selection of resistant parasites. plos.orgmmv.org

Computational models, including deep learning (DL)-based approaches, are being explored for predicting the activity of potential antischistosomal molecules. researchgate.net These models can analyze large datasets of chemical structures and biological activity data to identify patterns and predict the likelihood of a compound being effective against the parasite or a specific target like SmTGR. researchgate.net

Modeling of resistance mechanisms is also a critical area of research. While widespread clinical resistance to this compound is not yet common, laboratory studies have successfully induced resistance in schistosomes under drug pressure. frontiersin.org Understanding the genetic and molecular changes associated with this induced resistance, such as alterations in drug metabolism enzymes like cytochrome P450 or transport proteins like p-glycoprotein, can inform predictive models for monitoring and managing resistance in the field. core.ac.uk

Design and Evaluation of Next-Generation this compound Derivatives and Hybrid Compounds

The design and synthesis of new this compound derivatives and hybrid compounds represent a significant effort to develop next-generation treatments. The goal is to create molecules with improved efficacy, broader spectrum of activity (including against juvenile stages), enhanced pharmacokinetic properties, or reduced potential for resistance. plos.orgresearchgate.netmdpi.com

Molecular hybridization, which involves combining structural features of two or more known drugs or pharmacologically active compounds, is a strategy being used to design novel agents with potential dual activity or improved properties. researchgate.netmdpi.com For instance, molecular hybrids combining elements of this compound with other scaffolds have been synthesized and evaluated for antischistosomal activity. researchgate.netmdpi.com Some of these hybrids have shown promising activity against both newly transformed schistosomula and adult worms in in vitro studies. mdpi.com

Specific this compound derivatives are also being developed. One such derivative, designated P96, with a small structural modification (substitution of a cyclohexyl group with a cyclopentyl), has demonstrated broad-spectrum antischistosomal activity, notably improved efficacy against immature stages of Schistosoma japonicum compared to this compound. plos.org

Research into this compound Combination Therapies with Other Anthelmintics

Combining this compound with other anthelmintics is a strategy to enhance efficacy, broaden the spectrum of activity, and potentially mitigate the development of resistance. nih.govresearchgate.netresearchgate.net This approach leverages the different mechanisms of action and target stages of various drugs.

Studies have investigated the co-administration of this compound with artemisinin derivatives, which are effective against juvenile schistosomes, whereas this compound primarily targets adult worms. nih.govliberty.edu Experiments in animal models have shown that combined treatment with this compound and artemether can result in significantly higher worm reduction rates compared to single-drug treatments. nih.gov

Combination therapies are also being explored for treating other parasitic infections. A combination anthelmintic containing this compound along with ivermectin, pyrantel pamoate, and fenbendazole has been evaluated for efficacy against monogenean parasites in fish. researchgate.net

Clinical trials have also assessed combination regimens for treating soil-transmitted helminth infections and schistosomiasis. For example, studies have evaluated the effectiveness of this compound combined with albendazole, showing improvements in reducing the prevalence of various helminth infections. lshtm.ac.uk

Exploring this compound Activity Against a Broader Spectrum of Parasitic Organisms

While primarily known for its efficacy against trematodes and cestodes, there is ongoing interest in exploring this compound's activity against a broader spectrum of parasitic organisms. core.ac.ukbrighton.ac.uk

Beyond its well-established uses against Schistosoma species, Clonorchis sinensis, Opisthorchis viverrini, and certain tapeworms like Taenia solium and Taenia saginata, research is exploring its effects on other parasites. core.ac.ukbrighton.ac.uk This includes investigations into its potential activity against other flatworms like planarians and even some unicellular parasites such as Giardia species, although these areas require more controlled scientific study. core.ac.uk

Furthermore, the identification of TRPMPZQ as a target for this compound in schistosomes and other PZQ-sensitive parasites suggests that orthologs of this channel in other organisms could be potential targets, opening avenues for exploring this compound's activity in unexpected areas. frontiersin.orgresearchgate.net

Synergistic Approaches Combining this compound Chemotherapy with Vaccine Development Efforts

Integrating this compound chemotherapy with vaccine development efforts is considered a promising synergistic approach for schistosomiasis control. oup.comnih.govpeerj.comcambridge.orgresearchgate.net While this compound is effective in treating existing infections, it does not prevent reinfection, which is a major challenge in endemic areas. oup.complos.orgpeerj.com Vaccines aim to induce protective immunity and reduce worm burden or pathology. oup.comnih.govpeerj.com

Research suggests that this compound treatment can interact with the host immune response. oup.comnih.govcambridge.org this compound's action on the parasite tegument exposes worm antigens to the host immune system, potentially enhancing the immune response. oup.comnih.gov Studies have investigated combining this compound treatment with vaccination strategies using candidate antigens like the 28-kDa glutathione S-transferase (Sm28GST). oup.compeerj.com Experiments in animal models have shown that immunization with certain antigens combined with subcurative this compound treatment can lead to a greater reduction in worm burden than either intervention alone, suggesting a synergistic effect. peerj.comcambridge.org

This integrated approach, termed vaccine-linked chemotherapy, is being explored to leverage the strengths of both interventions: chemotherapy to reduce the existing parasite burden and vaccination to prevent or reduce reinfection and pathology. researchgate.net Understanding the complex immunological interactions between the vaccine, the parasite, and this compound is crucial for designing effective integrated control programs. nih.gov