Triclabendazole

Treatment of Fascioliasis

Clinical Efficacy

Triclabendazole is the drug of choice for treating fascioliasis. Studies have demonstrated high cure rates following treatment:

• Cure Rates by Dosage :

  Dosage Regimen	Cure Rate (%)	Study Reference
  10 mg/kg (single dose)	70% - 100%
  20 mg/kg (two doses)	96%
  10 mg/kg (multiple doses)	63% - 88%

In a retrospective cohort study involving children in Peru, the initial treatment with this compound resulted in a 55% cure rate , which decreased with subsequent treatments, indicating potential resistance or treatment failure in endemic areas .

Case Studies

• Case Study Example : In a report involving multiple cases of chronic fascioliasis, patients underwent several rounds of treatment with varying dosages of this compound. Despite initial improvements, many continued to shed Fasciola eggs post-treatment, highlighting challenges in achieving complete parasitological cure .

Potential Applications in Schistosomiasis

Recent studies have evaluated this compound's efficacy against Schistosoma mansoni , particularly in patients with co-infections of fascioliasis and schistosomiasis. A field survey showed that:

• Cure Rate for Schistosomiasis :
  • After two doses of this compound, the cure rate was 32.7% for schistosomiasis compared to 96% for fascioliasis .
• In Vitro Studies : this compound demonstrated significant effects on adult schistosomes, leading to rapid destruction of their tegument within hours .

Cancer Research

Emerging research suggests that this compound may have applications in oncology:

• Mechanism of Action : It has been shown to induce pyroptosis—a form of programmed cell death—in breast cancer cells by activating caspase-3 pathways. This mechanism involves the elevation of reactive oxygen species and the regulation of apoptotic proteins .
• Tumor Volume Reduction : In xenograft models, this compound significantly reduced tumor volumes, indicating its potential as an anti-cancer agent .

Resistance and Treatment Challenges

Despite its efficacy, there are growing concerns regarding resistance to this compound:

• A study reported that higher baseline egg counts and lower socioeconomic status were associated with treatment failure in children with chronic fascioliasis . This underscores the need for ongoing surveillance and research into alternative treatments or combination therapies to combat resistance.

Target of Action

Triclabendazole is an anthelmintic drug primarily used to treat fascioliasis, a parasitic infection often caused by the helminths, Fasciola hepatica and Fasciola gigantica . These parasites, also known as “the common liver fluke” or “the sheep liver fluke”, can infect humans following ingestion of larvae in contaminated water or food .

Mode of Action

This compound and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica . The drug and its active metabolites are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential, inhibition of motility, and disruption of the surface as well as ultrastructure that include inhibition of spermatogenesis and vitelline cells .

Biochemical Pathways

This compound is a member of the benzimidazoles and is generally accepted to bind to beta-tubulin, therefore preventing the polymerization of microtubules . This inhibition of tubulin polymerization and protein and enzyme synthesis disrupts the cell’s structural and functional capacity . Additionally, this compound has been found to decrease the intracellular level of cyclic AMP by inhibiting adenylyl cyclase .

Pharmacokinetics

Following a single 10-mg/kg dose of oral this compound given with a meal, peak plasma concentrations of unchanged drug and active sulfoxide metabolite (this compound sulfoxide) are attained within 3–4 hours . Food enhances the absorption of this compound , indicating that its bioavailability is influenced by dietary intake.

Result of Action

The result of this compound’s action is the effective treatment of fascioliasis. The drug’s interaction with its targets leads to the death of the parasites, thereby curing the infection . This compound has been shown in clinical studies to be effective in the treatment of chronic and acute forms of fascioliasis and in both F. hepatica and F. gigantica infections .

Action Environment

The efficacy of this compound can be influenced by environmental factors. For instance, the drug is more effective when administered with food, which enhances its absorption . Furthermore, the prevalence of fascioliasis is higher in areas with contaminated water or food, indicating that environmental sanitation plays a crucial role in the control and prevention of the disease .

Biochemical Properties

Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths . It is mainly metabolized by the CYP1A2 enzyme into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase) .

Cellular Effects

This compound has been found to induce lytic cell death in MCF-7 and MDA-MB-231 breast cancer cells, a typical sign of pyroptosis . It activates apoptosis by regulating the apoptotic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP . In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3 .

Molecular Mechanism

The molecular mode of action of this compound consists in binding to beta-tubulin, therefore preventing the polymerization of microtubules . This disrupts the structural integrity of the helminths, leading to their death .

Temporal Effects in Laboratory Settings

In a study on 350 individuals with metabolic syndrome high-risk, after a 3-month proactive intervention, two-thirds of the phenotypic markers were significantly improved in the cohort . This suggests that this compound has a time-dependent effect on biochemical markers.

Dosage Effects in Animal Models

In veterinary medicine, this compound is typically administered at an oral dose of 10 or 12 mg/kg body weight to sheep and cattle, respectively . The effects of this compound vary with different dosages in animal models. For example, in a study on sheep naturally infected with Fasciola sp., treatment with this compound resulted in significant reduction in fecal egg count .

Metabolic Pathways

This compound is metabolized within the host, principally into its sulphoxide and sulphone metabolites . This biotransformation is carried out by the flavin monooxygenase (FMO) and cytochrome P450 (CYP 450) enzyme systems .

Transport and Distribution

This compound and its metabolites are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential . This suggests that this compound is transported and distributed within cells and tissues via absorption.

Subcellular Localization

Given its mechanism of action, it is likely that this compound and its metabolites localize to regions where beta-tubulin is abundant, such as the cytoskeleton of cells .

Voies de synthèse et conditions de réaction

Le triclabendazole peut être synthétisé en utilisant diverses méthodes. Une méthode courante consiste à commencer par le 1,2,3-trichlorobenzène, qui subit une hydrolyse dans une liqueur alcaline à haute concentration pour former le 2,3-dichlorophénol de sodium . Cet intermédiaire réagit avec la 4,5-dichloro-2-nitroaniline dans une solution aqueuse de méthylbenzène pour former la 4-chloro-5-(2,3-dichlorophénoxy)-2-nitroaniline . Le groupe nitro est ensuite réduit par une méthode de transfert catalytique d'hydrogène, et le composé résultant subit une méthylation pour donner du this compound .

Une autre méthode consiste à utiliser la 3,4-dichloroaniline comme matière de départ, suivie d'une acylation, d'une nitration, d'une hydrolyse, d'une condensation, d'une réduction avec l'hydrate d'hydrazine et d'une fermeture de cycle avec le sulfate de S-méthylisothiourée . Cette méthode évite l'utilisation de réactifs dangereux et de réactions à haute pression, ce qui la rend plus sûre et plus respectueuse de l'environnement .

Méthodes de production industrielle

La production industrielle du this compound suit généralement les voies de synthèse mentionnées ci-dessus, avec des optimisations pour la fabrication à grande échelle. L'utilisation de matières de départ peu coûteuses et facilement disponibles, ainsi que de réactifs respectueux de l'environnement, rend le processus rentable et adapté à la production à grande échelle .

Types de réactions

Le triclabendazole subit diverses réactions chimiques, notamment :

Oxydation : Le this compound est métabolisé dans le foie pour former des métabolites sulfone et sulfoxyde.

Réduction : Le groupe nitro du composé intermédiaire est réduit en groupe amine pendant la synthèse.

Substitution : La synthèse implique des réactions de substitution nucléophile aromatique pour introduire le groupe dichlorophénoxy.

Réactifs et conditions courantes

Oxydation : Les enzymes hépatiques catalysent l'oxydation du this compound en ses métabolites.

Réduction : Le transfert catalytique d'hydrogène ou l'hydrate d'hydrazine est utilisé pour la réduction du groupe nitro

Substitution : Une liqueur alcaline à haute concentration et une solution aqueuse de méthylbenzène sont utilisées pour la substitution nucléophile aromatique.

Principaux produits formés

Métabolites sulfone et sulfoxyde : Formés lors de l'oxydation du this compound dans le foie.

4-chloro-5-(2,3-dichlorophénoxy)-2-nitroaniline : Un intermédiaire dans la synthèse du this compound.

Applications de la recherche scientifique

Le this compound a un large éventail d'applications de recherche scientifique :

Chimie : Utilisé comme composé modèle pour étudier les dérivés du benzimidazole et leurs propriétés chimiques.

Biologie : Étudié pour ses effets sur les douves du foie et autres organismes parasites.

Médecine : Principalement utilisé pour traiter la fascioliase et la paragonimiase chez l'homme et l'animal C'est le seul médicament approuvé par la FDA pour la fascioliase chez l'homme.

Industrie : Utilisé en médecine vétérinaire pour traiter les infections par les douves du foie chez le bétail.

Mécanisme d'action

Le this compound et ses métabolites sont absorbés par le tégument des douves du foie, entraînant une diminution du potentiel de membrane au repos et une inhibition de la motilité . Cette perturbation affecte la surface et l'ultrastructure des douves, conduisant finalement à leur mort . Le this compound se lie à la bêta-tubuline, empêchant la polymérisation des microtubules, ce qui est essentiel à la survie des douves .

Le triclabendazole est unique parmi les benzimidazoles en raison de son efficacité contre les douves du foie immatures et matures . Des composés similaires incluent :

Albendazole : Utilisé pour traiter une variété d'infections parasitaires, mais moins efficace contre les douves du foie.

Thiabendazole : Un autre dérivé du benzimidazole avec un mécanisme d'action différent, principalement utilisé pour traiter la strongyloïdose.

Closantel : Efficace contre les douves du foie immatures, mais pas aussi large spectre que le this compound.

La structure unique du this compound, y compris un noyau benzénique chloré et l'absence de groupe carbamate, contribue à son mécanisme d'action et à son efficacité distincts .

Triclabendazole (TCBZ) is a benzimidazole derivative that is primarily used as an anthelmintic agent for the treatment of infections caused by Fasciola hepatica and Fasciola gigantica. This compound exhibits a range of biological activities, particularly against helminths, and has garnered attention for its potential applications beyond parasitic infections. This article delves into the biological activity of this compound, presenting research findings, case studies, and a comprehensive analysis of its mechanisms of action.

The precise mechanism of action of this compound remains partially understood; however, several key pathways have been identified:

• Microtubule Disruption : TCBZ disrupts microtubule formation in helminths, leading to tegumental damage and impaired motility. This effect has been demonstrated in studies involving F. hepatica, where TCBZ exposure resulted in autophagic changes and loss of tubulin immunoreactivity in the tegumental syncytium .
• Metabolite Activity : The sulphoxide metabolite of TCBZ is believed to play a significant role in its efficacy. This metabolite exhibits delayed but potent effects on parasite motility and may act through multiple targets, including inhibition of adenylate cyclase activity .
• Oxidative Phosphorylation : There is evidence suggesting that TCBZ may uncouple oxidative phosphorylation, which could contribute to its anthelmintic effects .

Efficacy in Treating Fascioliasis

This compound is notably effective against all stages of Fasciola infections. A review of clinical studies indicates high cure rates following treatment with TCBZ:

Despite these high efficacy rates, treatment failures have been documented, particularly in cases with high baseline egg counts or lower socioeconomic status . A retrospective cohort study in Peru found that only 55% of children achieved parasitologic cure after the first round of treatment, with cure rates declining significantly after multiple doses .

Case Studies

Several case studies highlight the variability in treatment outcomes with this compound:

• Case Study 1 : A 51-year-old female farmer experienced significant weight loss and abdominal pain due to Fasciola infection. After initial treatment with TCBZ (10 mg/kg), her symptoms improved; however, she relapsed after eight months and continued shedding Fasciola eggs despite subsequent treatments .
• Case Study 2 : In another case involving chronic fascioliasis, a patient received multiple courses of TCBZ but failed to achieve sustained parasitologic cure, emphasizing the need for ongoing research into resistance mechanisms and alternative treatments .

Broader Biological Activities

Recent studies have also explored the antibacterial properties of this compound. Research indicates that TCBZ exhibits activity against certain Gram-positive bacteria, including methicillin-resistant strains. In combination with other agents, it has demonstrated synergistic effects against Gram-negative pathogens like E. coli and Klebsiella pneumoniae .