Triclabendazole

Elucidation of Triclabendazole Mechanism of Action

The pharmacological effects of this compound stem from its multifaceted interactions with critical cellular processes within the parasite. These interactions culminate in severe disruptions to the fluke's physiological integrity and viability.

Role of this compound Metabolites in Pharmacological Activity

This compound undergoes significant metabolism in the host, yielding active compounds that are primarily responsible for its anthelmintic efficacy.

Following oral administration, this compound is rapidly absorbed and undergoes extensive first-pass metabolism in the liver, primarily via the CYP1A2 enzyme (approximately 64%), to form its sulfoxide metabolite, this compound sulfoxide (TCBZ-SO). drugbank.comnih.govpatsnap.comfda.govijprajournal.com This metabolite is considered the primary active form due to its higher plasma concentrations and potent effects on parasite motility compared to the parent drug. drugbank.comijpsjournal.comnih.govpatsnap.comresearchgate.netfda.govijprajournal.commdpi.comresearchgate.net TCBZ-SO is highly prevalent in human plasma and is thought to be the main mediator of the drug's action. ijpsjournal.comnih.gov The plasma elimination half-life of this compound sulfoxide in humans is approximately 14 hours, contributing to its sustained therapeutic levels. fda.gov

This compound sulfoxide is further metabolized, mainly by CYP2C9, into another active metabolite, this compound sulfone (TCBZ-SO2). drugbank.comnih.govpatsnap.comfda.govresearchgate.net While also active, TCBZ-SO2 is generally present at lower plasma concentrations than TCBZ-SO. drugbank.comnih.govpatsnap.comfda.govmdpi.comresearchgate.net The plasma elimination half-life of this compound sulfone in humans is approximately 11 hours. fda.gov

Both this compound sulfoxide and this compound sulfone are absorbed by the tegument of the worms and contribute to the observed metabolic disturbances, including the reduction of resting membrane potential and inhibition of tubulin function, as well as protein and enzyme synthesis. drugbank.comfda.govmdpi.com The sulfoxide metabolite exhibits a more potent, albeit delayed, effect on parasite motility compared to the parent this compound. ijpsjournal.comnih.gov

Research indicates that the activity of these metabolites is dependent on their tissue concentration and duration of exposure. mdpi.com In studies comparing this compound-susceptible and -resistant Fasciola hepatica isolates, it has been observed that resistant flukes can metabolize this compound to its sulfoxide and then to the sulfone at a significantly higher rate than susceptible flukes. cambridge.orgconicet.gov.ar This increased metabolism of the sulfoxide to the less-active sulfone metabolite is one proposed mechanism of this compound resistance, leading to lower effective drug concentrations within the parasite. mdpi.comconicet.gov.ar

The relative plasma concentrations and half-lives of this compound and its key metabolites are summarized in the table below:

Comparative Pharmacodynamics of this compound with Other Anthelmintics

This compound stands out among anthelmintics due to its broad-spectrum efficacy against all stages of Fasciola species, including newly excysted juveniles, immature flukes, and adult flukes. researchgate.netijpsjournal.comnih.govpatsnap.com This characteristic is a significant advantage over many other trematodicidal drugs. For instance, some benzimidazole anthelmintics, such as albendazole, demonstrate activity primarily restricted to flukes older than 12 weeks. researchgate.net

Comparative studies assessing anthelmintic efficacy against Fasciola hepatica have highlighted this compound's superior performance. In controlled tests involving cattle, this compound at a dose of 12 mg/kg showed high mean efficacies against early immature (one-, two-, and four-week-old) fluke infections, ranging from 88.1% to 95.3%. nih.gov In contrast, albendazole, oxyclozanide, clorsulon, nitroxynil, and rafoxanide exhibited negligible or only slight to moderate activity against these early immature stages. nih.gov For older infections (six- and eight-week-old), this compound maintained high efficacies of 87.5% and 95.7%, respectively. nih.gov Against 10- or 12-week-old parasites, this compound demonstrated 100% efficacy, outperforming albendazole and oxyclozanide, which showed poor efficacy. nih.gov

A comparative analysis of anthelmintic treatments in sheep with fasciolosis reported this compound as the most effective anthelmintic with 97.8% efficacy, followed by Tetraclozan (96.6%) and Albendazole (84%). frontiersin.orgnih.gov While initial reduction rates might differ, the observed overlap in efficacy between this compound and Tetraclozan by day 21 suggests that this compound may have a faster onset of action, leading to a rapid reduction in parasite load, while other drugs might exhibit a slower, more sustained effect. frontiersin.orgnih.gov

The distinct pharmacodynamic profile of this compound, particularly its efficacy across all developmental stages of liver flukes, underscores its critical role as a frontline treatment for fascioliasis.

Absorption and Distribution Studies

The absorption and subsequent distribution of triclabendazole and its metabolites are critical determinants of its systemic exposure and efficacy. These processes exhibit variations across different species.

Biotransformation Pathways

The biotransformation of this compound is a rapid process involving key metabolic pathways that generate active metabolites crucial for its anthelmintic activity.

Excretion Studies Across Species

The excretion of this compound and its metabolites primarily occurs via the biliary tract into the feces across various species, with minimal urinary excretion. fao.orgfao.orgdrugbank.comrooyandarou.comeuropa.eunoahcompendium.co.ukdefra.gov.uknoahcompendium.co.uk

Excretion Profile by Species:

Pharmacokinetic Parameter Variation and Influencing Factors

The pharmacokinetic parameters of this compound exhibit variations influenced by species, dose, and other physiological factors.

Pharmacokinetic Parameters Across Species:

Influencing Factors:

Food: In humans, the co-administration of this compound with a meal (approximately 560 calories) significantly increased the maximum plasma concentration (Cmax) and area under the curve (AUC) of both this compound and its sulfoxide metabolite by about 2 to 3 times. drugbank.com

Dose: In rats, the peroral absorption of this compound was nearly complete at lower doses (1 mg/kg body weight) but decreased to approximately 50% at higher doses (10 mg/kg body weight). fao.org In rabbits, systemic exposure to the metabolites increased disproportionately with increasing oral doses. fao.org

Formulation: Studies in sheep indicated that the absorption of this compound from an aqueous suspension was similar to that from a peanut oil formulation. fao.org

Species Variation: Significant differences in pharmacokinetic parameters, including absorption, peak plasma concentrations, half-lives, and excretion patterns, are observed across various animal species such as humans, rats, rabbits, sheep, goats, and cattle. fao.orgfao.orgfao.orgconicet.gov.arnih.govinchem.orgdrugbank.comrooyandarou.comeuropa.eunoahcompendium.co.ukdefra.gov.uknoahcompendium.co.ukveyongpharma.comresearchgate.netnih.gov

Individual Variability: While intra-animal variability in the pharmacokinetic behavior of this compound was noted as small in sheep, inter-animal variability was found to be large. fao.org

Ruminal Entry: When orally administered to ruminating sheep, this compound generally enters the rumen, which can influence its subsequent biotransformation. fao.org

Interactive Data Tables: The data presented in the above tables are intended to be interactive, allowing for detailed comparison of pharmacokinetic parameters across different species and under various conditions.

Epidemiology and Prevalence of Triclabendazole Resistance

The escalating prevalence of this compound resistance in Fasciola species is a critical issue impacting both veterinary and human public health. This resistance has been documented across various geographical regions, driven largely by the extensive and often sole use of TCBZ for fascioliasis control. avensonline.orgavensonline.orgresearchgate.netresearchgate.netresearchgate.net

Mechanisms of this compound Resistance

Understanding the mechanisms by which Fasciola species develop resistance to this compound is crucial for developing effective control strategies. While the exact mechanisms are still being elucidated, research points to several key factors, including alterations in drug uptake and efflux, and changes in drug metabolism. avensonline.orgavensonline.orgnih.govfrontiersin.org

Detection and Monitoring of this compound Resistance

The detection and monitoring of anthelmintic resistance are critical for effective fascioliasis control and for implementing targeted treatment strategies nih.govwikipedia.orgnih.gov. However, the current landscape for detecting fluke resistance presents challenges, as there are no fully validated field-based methods, making confirmation difficult wikipedia.org. Despite these difficulties, various in vivo and in vitro methods are utilized or under active investigation to assess and monitor TCBZ resistance nih.govmims.comwikipedia.orgnih.govthegoodscentscompany.com.

Strategies to Mitigate and Manage this compound Resistance

The emergence of this compound resistance necessitates a multi-faceted approach to mitigate its impact and manage fascioliasis effectively. Strategies focus on a combination of judicious drug use, alternative treatments, and improved farm management practices. wikipedia.orgfrontiersin.orgnih.gov

Key strategies include:

Limiting Treatment Frequency: Reducing the number of TCBZ treatments can help slow down the selection pressure for resistant fluke populations. wikipedia.org

Strategic Dosing: Implementing dosing regimens based on epidemiological data and the lifecycle of the parasite can optimize efficacy and minimize resistance development. wikipedia.org

Correct Dosage: Ensuring accurate dosage is critical, as under-dosing can lead to sub-lethal drug concentrations that promote the survival and proliferation of resistant parasites. wikipedia.org

Anthelmintic Rotation and Combination Therapy: Rotating anthelmintics from different chemical groups annually can prevent the build-up of resistance to a single class of drugs. wikipedia.org More effectively, using combinations of drugs, particularly dual-active flukicides, can be highly beneficial, especially when the efficacy of individual drugs is compromised by resistance. wikipedia.org

Alternative Anthelmintics: Exploring and utilizing alternative drugs is crucial. While some alternatives like Albendazole and Clorsulon have also faced resistance issues, others such as Nitazoxanide have shown promising results. fishersci.ca Closantel is another alternative that has demonstrated efficacy against TCBZ-resistant F. hepatica in some cases. mims.commims.com

Vaccine Development: Ongoing research into developing effective vaccines against Fasciola species could significantly reduce fluke burdens, irrespective of drug resistance. wikipedia.orgfishersci.ca Candidate antigens like Leucine aminopeptidase and Glutathione-S-transferase have shown protective effects in sheep and goats, respectively. fishersci.ca

Integrated Parasite Management: Implementing control methods beyond chemotherapy is vital. This includes:

Intermediate Host Control: Reducing the population of intermediate hosts, such as mud snails, through measures like lowering groundwater levels, improving drainage, and cleaning ditches. wikipedia.orgmims.com

Pasture Management: Reducing exposure to infection by managing fluke-prone areas, including alternative land use and fencing off high-risk pastures. wikipedia.orgmims.com

Biological Control: Investigating and implementing biological control measures against mud snails and pasture larvae. cabidigitallibrary.org

Accessible Guidelines and Accurate Diagnosis: Providing accessible guidelines for anti-parasitic drug administration to concerned staff and ensuring accurate diagnosis and identification of drug-resistant fluke populations are fundamental to effective control and conservation of drug efficacy. fishersci.canih.gov

These integrated strategies are essential to combat this compound resistance and ensure sustainable control of fascioliasis.

Efficacy Against Fasciola Species (F. hepatica and F. gigantica)

Triclabendazole exhibits high effectiveness against infections caused by both Fasciola hepatica and Fasciola gigantica nih.gov. This broad activity is a key characteristic that distinguishes it from many other anthelmintics scielo.brmdpi.comajpbp.com.

This compound is notable for its broad activity against various developmental stages of Fasciola hepatica, showing efficacy from two-day-old immature flukes through to mature adult parasites mdpi.comjarvm.com. This is particularly important as immature flukes are responsible for significant tissue damage during their migration scielo.br.

Efficacy Data in Animal Models:

In sheep, a 10 mg/kg dose of this compound achieved 99% efficacy against F. hepatica flukes aged between 1 and 12 weeks nih.gov.

Studies in sheep demonstrated varying efficacy based on dose and fluke age for F. hepatica:

At 2.5 mg/kg, efficacy was 90% against 8-week-old flukes and 98% against 12-week-old flukes scilit.com.

At 5 mg/kg, efficacy was 92% against 4-week-old flukes, 98% against 8-week-old flukes, and 100% against 12-week-old flukes scilit.com.

At 10 mg/kg, efficacy ranged from 93-98% against 1-week-old flukes and 99-100% against 2-4-week-old flukes scilit.com.

At 15 mg/kg, 98% efficacy was observed against flukes one day post-infection scilit.com.

For Fasciola gigantica, this compound showed 100% efficacy against immature flukes in rabbits and sheep, based on fluke recovery. In goats, the efficacy was 95.7% against 4-week-old flukes and 100% against 6-week-old flukes researchgate.net.

In naturally infected sheep with Fasciola species (F. hepatica and F. gigantica), fecal egg count reductions of 96.51% at 14 days and 97.18% at 21 days post-treatment were observed veteringroup.us.

Table 1: Efficacy of this compound Against Fasciola hepatica in Sheep by Fluke Age and Dose

Table 2: Efficacy of this compound Against Fasciola gigantica in Various Animals

Clinical Efficacy in Human Fascioliasis

This compound is highly effective in the treatment of human fascioliasis, applicable to both adults and children, and across all stages and forms of infection nih.govoup.com. It is considered the drug of choice for human fascioliasis oup.comwho.intpaho.orgwho.int. Its high efficacy has been consistently demonstrated in clinical trials conducted over a 25-year period, as well as in numerous case reports oup.com.

Clinical trials have reported high cure rates and significant egg reduction rates following this compound treatment. Early studies by Ciba/WHO showed that a 10 mg/kg dose (administered as a single dose or two 5 mg/kg doses) yielded cure rates ranging from 70% to 100% in both adult and pediatric patients nih.govoup.com. A total dose of 20 mg/kg (given as two 10 mg/kg doses on Days 1 and 3) also resulted in very high cure rates nih.govoup.com.

In a study involving schoolchildren in Bolivia, cure rates were 77.8% after one treatment and increased to 97.8% after two treatments. Corresponding egg reduction rates ranged from 74% to 90.3% after one treatment and from 84.2% to 99.9% after two treatments plos.org. Another review cited cure percentages of 79.4–83% with a single 10 mg/kg dose and 92.2–93.9% with two 10 mg/kg doses administered 12 hours apart. Egg reduction rates were reported as 74–90.3% after one treatment and 84.2–99.9% after two treatments paho.org.

For chronic fascioliasis, a single oral dose of 10 mg/kg resulted in 79.2% (19/24) of patients being egg-negative two months post-treatment. Retreatment of three of five cases that initially failed achieved parasitologic cure ajtmh.org. In Peruvian children, a study reported a 100% parasitological cure rate with two 7.5 mg/kg doses given 12 hours apart, and 95% with a single 10 mg/kg dose, with re-treatment successfully curing the two initial failures scielo.br.

However, some studies have reported lower efficacy, particularly in areas where resistance may be emerging. For instance, a study in children with chronic fascioliasis in Peru showed a 55% cure rate after the first treatment, with declining rates after subsequent treatments (38% after the second, 30% after the third, and 23% after the fourth) nih.gov. Cases of treatment failure have been documented, raising concerns about potential drug resistance mdpi.complos.org.

Table 3: Summary of Cure Rates in Human Fascioliasis Clinical Trials

Table 4: Summary of Egg Reduction Rates (ERR) in Human Fascioliasis Clinical Trials

This compound has demonstrated efficacy in treating both acute and chronic forms of human fascioliasis nih.govresearchgate.net. In one study focusing on patients with acute fascioliasis, cure rates at 60 days were reported as 63.9% for a single 10 mg/kg dose, 68.6% for two 10 mg/kg doses, and 63.9% for three 10 mg/kg doses nih.gov. For chronic human fascioliasis, a study found a 94% cure rate at two months when assessed by the disappearance of eggs in stools, and 88% when assessed by both the absence of eggs and worms in the biliary system who.int.

The administration of this compound with food, particularly a fatty meal, is generally recommended nih.gov. Early studies indicated that a single 10 mg/kg dose, when given postprandially, is typically effective nih.gov. In some Ciba/WHO studies, doses administered under fed conditions resulted in cure rates ranging from 80% to 96% nih.gov. A study in Cuba also involved treating patients with two 10 mg/kg doses given after food nih.gov. Conversely, one study noted that administering this compound after an overnight fast might have influenced drug absorption, potentially contributing to a cure rate of 79.2% ajtmh.orgscielo.br. Another study that used a post-prandial dose in children reported a 77.5% cure rate scielo.br.

Efficacy in Animal Fascioliasis

This compound has demonstrated high efficacy across a range of animal species affected by fascioliasis, including cattle, buffaloes, sheep, goats, and rabbits. Its effectiveness varies depending on the host, the Fasciola species, and the developmental stage of the fluke.

In cattle and buffaloes, this compound has shown significant effectiveness. A comparative study indicated that this compound was highly effective against Fasciola sp., achieving 97.92% efficacy in cattle and 100% in buffaloes at 21 days post-medication, surpassing the efficacy of other anthelmintics like Oxyclozanide and Nitroxynil. nih.govfishersci.be Against Fasciola hepatica in cattle, this compound exhibited varying efficacies based on the fluke's age: 88.1% against 1-week-old early immature flukes, 95.3% against 2-week-old flukes, and 90.7% against 4-week-old flukes. For more mature infections, efficacy was 87.5% against 6-week-old flukes and 95.7% against 8-week-old flukes. Against 10- or 12-week-old parasites, this compound achieved 100% efficacy. uni.lu In experimentally infected buffaloes with Fasciola gigantica, high efficacy (100%) was observed, leading to no fluke eggs in feces and no flukes recovered from the liver in certain studies. uni.lu More recently, a 2025 study in Côte d'Ivoire cattle found this compound to be significantly more effective (95.4%) than albendazole (70.3%) against Fasciola gigantica and Fasciola hepatica at day 21 post-treatment. wikidoc.org

For sheep, this compound has consistently shown high efficacy. In artificially infected sheep, it achieved 100% efficacy against 4- and 13-week-old Fasciola hepatica. nih.govnih.gov In naturally infected sheep, efficacy rates of 96.51% at 14 days and 97.18% at 21 days post-treatment have been reported against Fasciola sp. wikipedia.org Another study in sheep demonstrated this compound's efficacy at 97.8% against ovine fascioliasis. wikipedia.org When used in combination with Levamisole, this compound's efficacy against Fasciola sp. in naturally infected sheep reached 97.31% at 28 days, slightly higher than this compound alone (95.60%). wikipedia.org

In goats, this compound has also proven effective. Against Fasciola gigantica, it showed 95.7% efficacy against 4-week-old flukes and 100% against 6-week-old flukes. uni.lu In experimentally infected goats with Fasciola hepatica, the drug was highly effective against mature flukes (100%), late immature flukes (99.2%), and effective against early immature flukes (94.9%). nih.gov

Studies in rabbits have also indicated 100% efficacy of this compound against immature Fasciola gigantica. uni.lu

Despite its widespread effectiveness, instances of this compound resistance have been reported in various regions and animal populations, particularly in cattle and sheep. For example, studies in Peru and Chile have documented significantly lower efficacies, with one report in Peruvian cattle showing only 31.05% efficacy on day 14 and 13.63% on day 30, and another in Chilean cattle reporting 0% fecal egg count reduction even at double the usual dose. nih.govfishersci.ca Similarly, in a fascioliasis outbreak in Brazil, this compound showed reduced efficacy of 66.3% in sheep and 57.3% in goats. uni.lu

Table 1: Summary of this compound Efficacy in Animal Fascioliasis

Histopathological Assessments of this compound Efficacy

Histopathological evaluations provide critical insights into the direct effects of this compound on Fasciola flukes and the subsequent recovery or changes in host tissues. Studies have consistently shown that this compound induces significant morphological and structural damage to the parasite.

On the adult Fasciola hepatica fluke, this compound causes substantial disruption to both the tegument and the intestine. nih.govwikipedia.org Changes observed in the tegument include edema and swelling of its structural components, with the spines becoming enlarged, swollen, and more rounded, often showing increased eosinophilic dye perception. Surface blebbing and microvillus formation are also common features, indicative of a stress response by the fluke to the drug's action. nih.gov

Within the fluke's intestine, this compound leads to a detachment of the brush border of the intestinal epithelium and an accumulation of microvilli in the intestinal lumen. The cellular structures of the intestinal epithelium can appear melted, and the boundaries between layers become blurred, making it difficult to distinguish apical and basal parts. nih.gov These alterations underscore the drug's impact on the parasite's ability to absorb nutrients and maintain structural integrity.

Beyond the parasite itself, this compound treatment also influences host tissue pathology. In experimentally infected goats, early treatment (at 4 weeks post-infection) with this compound was found to prevent the development of both liver parenchyma and bile duct lesions. Treatment at 8 weeks post-infection primarily prevented bile duct lesions, while treatment at 16 weeks post-infection had no appreciable effect on the development of major hepatic lesions. nih.gov This suggests that early intervention is crucial for mitigating host tissue damage.

In rats, this compound treatment resulted in a reduction in liver lesions, with histopathological examinations revealing a largely normal appearance of hepatic structures. Minor changes observed included congestion and thrombosis of some hepatic vasculatures, as well as bile duct proliferation, hyperplasia, cholangitis, and pericholangitis, alongside focal granular degeneration in the hepatic parenchyma. nih.govuni.lu

Furthermore, this compound induces significant histological changes in the reproductive organs of susceptible Fasciola hepatica flukes, such as the testes, ovary, and vitelline tissue. These lesions are well-developed by 72 hours post-treatment and include strong positive labeling for apoptosis in morphologically abnormal cells undergoing mitosis or meiosis. In contrast, flukes recovered from field outbreaks suspected of this compound resistance showed no significant histological changes or evidence of apoptosis, highlighting the utility of histopathology in assessing drug resistance. nih.govnih.gov The co-incubation of this compound with P-glycoprotein inhibitors has been shown to enhance disruption to the fluke's tegumental syncytium and cells, leading to increased vacuolation, sloughing, and spine disruption, suggesting that drug transporters may contribute to the development of drug resistance. indiamart.com

Novel Formulations of Triclabendazole

This compound is classified as a Class II/IV compound under the Biopharmaceutical Classification System due to its poor water solubility (0.24 μg/mL), which poses a significant challenge for developing effective dosage forms and limits its therapeutic effect. plos.orgresearchgate.net To overcome this, significant efforts have been directed towards developing novel drug delivery systems that enhance its solubility, dissolution rate, and ultimately, its bioavailability and efficacy. plos.orgresearchgate.netleeds.ac.ukdataintelo.comconicet.gov.ar

One promising approach involves nanotechnology, utilizing "soft" nanotechnology and nanomedicine. plos.orgleeds.ac.uk Researchers have developed chitosan-based nanocapsules and nanoemulsions of this compound. plos.orgleeds.ac.ukresearchgate.net These formulations produce capsules less than one micron in size, loaded with this compound and coated with chitosan, a naturally occurring sugar polymer. leeds.ac.uk This nanocapsule form can increase the drug's solubility by up to 100 times compared to its traditional tablet form, leading to more efficient and rapid absorption. leeds.ac.uk Studies have shown that the release of TCBZ from these nanoformulations in simulated gastric fluid was 9 to 16-fold higher than from an untreated TCBZ dispersion. plos.orgresearchgate.net

Another strategy involves complexing this compound with cyclodextrins, such as 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) and methyl-β-cyclodextrin (Me-β-CD). conicet.gov.ar This complex formation significantly improves the aqueous solubility of this compound, with enhancements up to 256-fold using HP-β-CD and 341-fold using Me-β-CD. conicet.gov.ar The drug dissolution rate was also improved, particularly with 1:2 M ratio complexes exhibiting higher dissolution than 1:1 M ratio complexes. conicet.gov.ar These complexes demonstrated strong evidence of amorphous phases or inclusion complex formation, which remained stable for 24 months at room temperature. conicet.gov.ar

Furthermore, the development of this compound nanoparticles using methods like hot homogenization has shown potential. wjarr.comresearchgate.net Formulations using stearic acid as a lipid, beeswax as a wax, and poloxamer 188 as a surfactant have yielded nanoparticles with entrapment efficiencies ranging from 44.63% to 83.15%. wjarr.comresearchgate.netwjarr.com These nanoparticles exhibited a spherical shape and smooth morphology, with in vitro release studies showing a sustained drug release over 9 hours in pH 7.4 PBS. wjarr.comresearchgate.netwjarr.com These advancements aim to improve intestinal absorption and potentially reduce side effects. wjarr.comresearchgate.net

Recent innovations also include long-acting injectables and oral drench solutions, which offer improved ease of administration and sustained protection against parasites, making this compound a more appealing option in veterinary medicine. marketresearchintellect.com

Combination Therapies with this compound

Combining this compound with other anthelmintics or antimicrobial agents is an active area of research, aiming to enhance efficacy, combat drug resistance, and broaden the spectrum of activity. google.comscielo.org.co This approach can lead to synergistic effects, allowing for reduced dose rates and potentially lower production costs. google.com

Repurposing this compound for Other Pathogens

Drug repurposing, or repositioning, involves investigating existing compounds with known safety profiles for new therapeutic applications, offering a faster and more cost-effective path to developing new treatments. researchgate.netnih.gov this compound has shown promising activity against various bacterial pathogens, including multidrug-resistant (MDR) strains. researchgate.netnih.govnih.gov

Synthesis and Evaluation of this compound Derivatives

The synthesis and evaluation of this compound derivatives represent an important area of research aimed at developing new compounds with enhanced or broader therapeutic activities, particularly in the context of anthelmintic resistance. nih.govnih.govnih.gov

One notable derivative, referred to as "Compound Alpha," has demonstrated significant promise as a flukicide. This derivative exhibits a similar range of activity to TCBZ against Fasciola hepatica, proving effective against all developmental stages of the parasite, from 3 days to 12 weeks post-infection. nih.gov Its mechanism of action is believed to involve β-tubulin antagonism, a common mode of action for benzimidazole anthelmintics. nih.gov

Structure-activity relationship (SAR) investigations are crucial in understanding how modifications to the this compound scaffold influence its biological activity. For instance, studies on hederagenin derivatives have explored their ex vivo anthelmintic potential against Fasciola hepatica newly excysted juveniles (NEJs). nih.gov Among 36 tested hederagenin derivatives, eleven showed activity against NEJs, indicating the importance of specific structural features for efficacy. nih.gov

Beyond anthelmintic applications, benzimidazole derivatives, including those structurally related to this compound, are being explored for other biological activities. Research has focused on their potential as antitubercular agents, with some derivatives showing moderate activity against various bacteria and fungi, including Candida.

Application of Metabolomics in Triclabendazole Action Studies

Metabolomics, a comprehensive "whole-organism assay approach," is increasingly applied to identify metabolic perturbations within cells and organisms following exposure to drugs like this compound. This technique utilizes analytical methods such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) to identify and quantify a wide array of metabolic compounds. ijprajournal.comavensonline.org

For Fasciola hepatica, metabolomic profiling has been employed to compare the metabolic responses of different clonal isolates when exposed to this compound. ukri.org Such studies are instrumental in uncovering the intricate biochemical pathways affected by the drug, thereby providing insights into its mode of action and the mechanisms of drug resistance. ukri.org The precise mechanism of action for this compound is complex and is believed to involve multiple targets. In vitro and in vivo studies suggest that this compound and its active metabolites, sulfoxide and sulfone, are absorbed through the outer body covering (tegument) of immature and mature worms. This absorption leads to a reduction in the resting membrane potential, inhibition of tubulin function, and disruption of protein and enzyme synthesis essential for parasite survival. drugbank.commdpi.com These metabolic disturbances collectively impair motility, disrupt the worm's outer surface, and inhibit critical processes such as spermatogenesis and the development of egg/embryonic cells. drugbank.commdpi.com

Affinity Purification for Target Protein Identification

Affinity purification stands as a powerful technique for identifying the specific biological targets of small molecules by directly revealing their physical interactions with biomolecules. nih.gov This method involves immobilizing the small molecule, such as this compound, onto a solid support. A protein extract is then passed over this support, allowing specific target proteins with binding affinity to the immobilized ligand to bind. After washing away non-bound components, the target proteins are eluted and subsequently identified, often through mass spectrometry. ijprajournal.comthermofisher.com

While highly effective, a key challenge in affinity purification is distinguishing true specific targets from non-specific background interactions. nih.gov In the context of this compound research, affinity purification of putative protein targets has been proposed to further delineate its mode of action. ijprajournal.com Proteomic investigations, which complement affinity purification, have identified differences in the inherent proteome profiles of various F. hepatica isolates. These studies have highlighted this compound-responding proteins, including glutathione transferase and fatty acid binding protein (FABP), which have been shown to bind this compound sulfoxide (TCBZ-SO) at physiologically relevant concentrations. researchgate.net FABP, in particular, is considered a strong candidate for its potential role in this compound metabolism and resistance. researchgate.netplos.org

Functional Genomics and Genetic Experiments for Resistance Understanding

Understanding the genetic basis of this compound resistance is critical due to its widespread emergence and impact on effective parasite control. Functional genomics and genetic experiments are extensively employed to investigate these mechanisms in Fasciola hepatica. ukri.orgplos.orgnih.govcambridge.org

Research in this area often involves experimental crosses between this compound-susceptible and this compound-resistant F. hepatica clones, followed by mapping resistance genes across subsequent F1 and F2 generations. plos.orgnih.govcambridge.org These studies have successfully identified a major genetic locus, approximately 3.2 Mbp in size within the 1.2 Gbp F. hepatica genome, that confers this compound resistance and exhibits dominant Mendelian inheritance. plos.org

Within this identified locus, several candidate genes have been pinpointed, including those associated with:

Membrane transport: Such as the ATP-binding cassette family B (ABCB1). plos.org

Transmembrane signaling and signal transduction: Including GTP-Ras-adenylyl cyclase and EGF-like protein. plos.org

DNA/RNA binding and transcriptional regulation: For instance, SANT/Myb-like DNA-binding domain proteins. plos.org

Drug storage and sequestration: Such as fatty acid binding protein (FABP). plos.org

Genome-wide analysis and bulk segregant analysis of F. hepatica populations have been instrumental in validating these genetic loci, confirming their role as targets of drug selection in field populations. plos.orgcambridge.orgresearchgate.net Furthermore, studies have indicated lower levels of gene expression in this compound-resistant F. hepatica (both juvenile and adult stages) within a specific region containing 15 genes implicated in conferring resistance. ukri.org

Bioluminescent Mouse Models in Efficacy Studies

Bioluminescent mouse models represent a powerful tool in infectious disease research, enabling the quantification and localization of pathogens or host cells in vivo. frontiersin.org These models have been particularly valuable in assessing the efficacy of this compound, especially in studies exploring its potential repurposing as an antibacterial agent. mdpi.comnih.govresearchgate.netnih.gov

For instance, a bioluminescent mouse model of Staphylococcus aureus sepsis has been utilized to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this compound. mdpi.comnih.govresearchgate.netnih.gov In such studies, oral administration of this compound resulted in a significant reduction in S. aureus populations in the bloodstream, consistent with a bacteriostatic effect in vivo. mdpi.comnih.govresearchgate.netnih.gov The use of bioluminescent models significantly accelerates the drug discovery process and facilitates a deeper understanding of host-pathogen interactions. frontiersin.org

In Vitro and In Vivo Model Systems for Research

A diverse array of in vitro and in vivo model systems are indispensable for comprehensive this compound research, allowing for controlled experimentation and the study of complex biological processes.

In Vitro Model Systems:

Drug Susceptibility and Metabolism: In vitro assays are used to study drug susceptibility and metabolism, including the development of innovative assays using hepatic spheroids to mimic the host liver's metabolic environment for F. hepatica studies. sydney.edu.aumdpi.com These systems allow for the co-culture of F. hepatica with this compound and its active metabolites (sulfoxide and sulfone) to investigate parasite-drug interactions. sydney.edu.au

Cytotoxicity and Cellular Uptake: Cell lines such as Caco-2 are employed for cellular uptake studies, while MCF-7 (human breast cancer), HEK293 (human embryonic kidney), and Detroit 562 (human pharyngeal epithelial) cell lines are used for cytotoxicity evaluations. mdpi.complos.org

Drug-Drug Interactions: Bovine liver microsomal fractions and precision-cut liver slices (PCLSs) serve as in vitro models to assess drug-drug interactions, such as those between this compound and fenbendazole. conicet.gov.ar

Mechanism of Action Elucidation: In vitro studies have shown that this compound and its active metabolites are absorbed by the outer body covering of worms, leading to a reduction in resting membrane potential, inhibition of tubulin function, and disruption of protein and enzyme synthesis. drugbank.commdpi.com this compound is primarily metabolized by CYP1A2 and, to a lesser extent, by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO into its active sulfoxide metabolite, which is further metabolized by CYP2C9 to the sulfone metabolite. ijprajournal.comdrugbank.com

In Vivo Model Systems:

Animal Models: Various animal models, including rats, mice, sheep, and cattle, are extensively utilized to study this compound's effects and resistance mechanisms. drugbank.commdpi.complos.orgnih.govnih.govnih.govresearchgate.net

Efficacy and Pharmacokinetic Studies: Bioluminescent mouse models are employed for in vivo efficacy studies, as detailed in Section 7.4. mdpi.comnih.govresearchgate.netnih.gov

Morphological and Resistance Studies: Rat models are used to observe morphological changes in F. hepatica following this compound treatment, sometimes in combination with metabolic inhibitors like ketoconazole, which can alter drug metabolism and diminish resistance. researchgate.net

Transporter Function and Drug-Drug Interactions: Murine Abcg2-transduced cells and mice are used to investigate in vivo transporter function, revealing interactions between this compound metabolites and ABCG2. nih.gov For example, this compound sulfoxide (TCBZSO) has been shown to affect nitrofurantoin secretion into milk in mice, indicating drug-drug interactions in vivo. nih.gov

Genetic Basis of Resistance: Experimental in vivo approaches are crucial for analyzing this compound resistance in F. hepatica within infected animals. nih.govcambridge.org

Interactive Data Tables

The following table presents Minimum Inhibitory Concentration (MIC) values for this compound (TCBZ) against various bacterial strains, as reported in studies investigating its antibacterial properties.

Note: N/A indicates that data for that specific condition were not reported in the source. PMB refers to Polymyxin B, used at sub-inhibitory concentrations. mdpi.comnih.govnih.gov

Addressing Unelucidated Mechanisms of Action

While triclabendazole and its active metabolites, this compound sulfoxide and this compound sulfone, are known to be absorbed by the tegument of Fasciola species, leading to a reduction in resting membrane potential, inhibition of tubulin function, and disruption of protein and enzyme synthesis, the precise mechanism of action remains incompletely understood drugbank.comnih.govmedscape.compatsnap.com. This lack of complete elucidation is a crucial research gap.

Current understanding suggests that TCBZ's action involves multiple targets, including the disruption of microtubule-based processes through binding to beta-tubulin, which is vital for cellular functions like maintaining cell shape, division, and intracellular transport nih.govpatsnap.commdpi.comresearchgate.net. Furthermore, the drug has been observed to interfere with the parasite's energy metabolism, specifically impacting key enzymes within the mitochondria, leading to a depletion of adenosine triphosphate (ATP) production patsnap.compatsnap.com. This dual action of metabolic disruption and tegumental damage contributes to the drug's potency patsnap.com.

Future research needs to focus on further pinpointing the primary molecular targets and detoxification pathways within the parasite to gain a more comprehensive understanding of TCBZ's efficacy and how resistance develops researchgate.netnih.gov. Identifying specific genetic variants linked to its mechanism of action could provide valuable insights for developing new diagnostic tools and therapeutic strategies ucd.ie.

Developing Strategies for Emerging Resistance

The emergence and widespread increase of this compound resistance in Fasciola hepatica populations in both livestock and humans represent a significant threat to global fascioliasis control efforts mdpi.comresearchgate.netnih.govucd.ienih.govavensonline.orgresearchgate.netresearchgate.netveterinary-practice.comcapes.gov.brnih.govcambridge.orgwur.nlfrontiersin.orgscielo.br. Resistance was first documented in animals in Australia in 1995, with human cases reported starting in 2012 researchgate.netnih.govresearchgate.netcapes.gov.brnih.govcambridge.org.

The mechanisms underlying TCBZ resistance are multifactorial. They include alterations in drug uptake and efflux mechanisms, such as those involving P-glycoprotein linked drug efflux pumps, modifications in target molecules, and changes in drug metabolism within the parasite drugbank.commdpi.comresearchgate.netavensonline.orgnih.govfrontiersin.orgplos.org. For instance, increased metabolism of this compound sulfoxide to the less active sulfone metabolite or enhanced glutathione S-transferase detoxification activity has been implicated mdpi.complos.org.

To combat this growing challenge, several strategies are being explored and recommended:

Strategic Dosing and Rotation: Limiting the frequency of treatments and implementing strategic dosing based on epidemiological data are crucial avensonline.org. Annual rotation of anthelmintics from different chemical groups is also advised to prevent the buildup of resistance to a particular class of drug avensonline.orgveterinary-practice.comscielo.br.

Combination Therapies: The use of drug combinations is a promising approach, particularly when the efficacy of individual drugs is compromised by resistance, as it can leverage synergistic effects avensonline.orgresearchgate.netnih.govscielo.brresearchgate.net.

Integrated Parasite Management (IPM): Implementing comprehensive IPM approaches that combine drug treatments with other control measures, such as pasture management, improved drainage, and biological control of intermediate host snails, is essential for sustainable control and to slow resistance spread nih.govresearchgate.netwur.nl.

Genetic Research: Advanced genetic analysis, including next-generation sequencing, is being utilized to identify genetic markers associated with resistance. This research aims to better understand the underlying biological processes of resistance, which can inform the development of molecular tests for early detection and targeted treatments ucd.ieplos.orgukri.orgnih.gov.

In Vitro Assays: Developing innovative in vitro drug metabolism assays is critical for studying resistance mechanisms and screening new anthelmintic compounds without relying heavily on animal models sydney.edu.au.

Further Pharmacokinetic and Pharmacodynamic Studies in Diverse Populations

Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of this compound is essential for optimizing its use and addressing variability in treatment outcomes. TCBZ is rapidly absorbed and metabolized in the liver to its primary active metabolite, this compound sulfoxide, and a less active metabolite, this compound sulfone drugbank.commedscape.commdpi.comfrontiersin.orgfda.govparasitipedia.netijpsjournal.comresearchgate.netinchem.org. The sulfoxide metabolite is considered the most active and abundant form in plasma mdpi.comparasitipedia.netijpsjournal.comresearchgate.netinchem.org. Peak plasma concentrations for TCBZ and its metabolites are reached at varying times, typically within hours of administration, and elimination half-lives range from approximately 8 to 14 hours in humans drugbank.commedscape.comfda.govinchem.org. TCBZ and its metabolites exhibit high protein binding, exceeding 96% fda.gov. Excretion primarily occurs via feces, with a smaller proportion in urine inchem.org.

Despite this general understanding, further PK/PD studies are crucial, particularly in diverse populations:

Pediatric and Vulnerable Populations: There is limited safety and efficacy data for TCBZ in children under six years of age, despite its administration in some cases nih.gov.

Patients with Organ Impairment: Studies on TCBZ pharmacokinetics in patients with renal or hepatic impairment are currently lacking fda.gov. Such studies are vital to establish appropriate dosing regimens for these patient groups.

Variability in Drug Response: Reported variability in drug response and efficacy among individuals suggests that factors such as altered drug uptake/efflux, metabolic differences, and environmental influences may play a role frontiersin.org.

Species-Specific PK: Pharmacokinetic parameters can differ significantly between host species (e.g., cattle versus sheep), and are also influenced by factors like dietary conditions fao.orgresearchgate.net. More comparative studies are needed to inform veterinary applications.

Infected vs. Healthy Subjects: While some studies in Egyptian patients have indicated no significant differences in certain PK parameters between infected and parasite-free individuals, further research across various endemic regions and patient cohorts is necessary to confirm these findings and explore other potential influences researchgate.net.

Repurposed Applications: For potential repurposed uses of TCBZ, such as its demonstrated antibacterial activity, comprehensive PK/PD profiling is essential to enhance its efficacy and guide pharmaceutical development mdpi.com.

Investigating Drug-Drug Interactions

The potential for drug-drug interactions (DDIs) with this compound is an important area for future research, particularly given its metabolic profile. Although formal clinical drug interaction studies have not been extensively conducted for TCBZ, in vitro data provide some insights fda.govdrugs.com.

Key findings regarding TCBZ's interaction potential include:

Cytochrome P450 (CYP) Inhibition: this compound and its sulfoxide and sulfone metabolites have the potential to inhibit CYP2C19, and to a lesser extent, CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 3A at clinically relevant plasma concentrations researchgate.netfda.govdrugs.com. This inhibition can lead to increased plasma concentrations of co-administered drugs that are substrates of CYP2C19 medscape.comfda.govdrugs.com.

QTc Prolongation: There is a potential for QTc interval prolongation when TCBZ is co-administered with other medications known to prolong the QTc interval drugbank.commedscape.comfda.govdrugs.com. Electrocardiogram (ECG) monitoring is advised in such cases drugbank.commedscape.comfda.govdrugs.com.

Interactions with Other Anthelmintics: Co-administration with ivermectin has been observed to result in higher peak plasma concentrations of TCBZ's sulfoxide and sulfone metabolites fao.org.

Future research should prioritize formal clinical drug interaction studies to comprehensively assess the impact of TCBZ on other medications and vice versa fda.govdrugs.com. A thorough assessment is particularly warranted for combination therapies to mitigate the risk of adverse clinical outcomes researchgate.net. Additionally, in vitro studies are needed to determine whether TCBZ and its metabolites induce CYP enzymes, which could further influence the metabolism of other drugs drugs.com.