Closantel

Closantel can be synthesized through various methods. One method involves the preparation of this compound sodium intermediate by catalytic hydrogenation . Another method includes the preparation of this compound sodium injection, which involves mixing ethanol and propylene glycol, heating the mixture, adding sodium this compound, and adjusting the pH with sodium hydroxide solution . These methods are efficient and suitable for industrial production.

Closantel undergoes several types of chemical reactions, including oxidation, reduction, and substitution. For example, the enantiomeric separation of this compound can be achieved using high-performance liquid chromatography (HPLC) with different chiral stationary phases and mobile phase compositions . The major products formed from these reactions are the enantiomers of this compound, which can be separated and analyzed for further research .

Antiparasitic Applications

Closantel is widely recognized for its effectiveness against various parasitic infections in ruminants, particularly against blood-feeding helminths such as Fasciola hepatica and Haemonchus contortus. It operates by inhibiting the metabolism of these parasites, leading to their death.

Efficacy Against Specific Parasites

• Fasciola spp. : this compound has shown a 100% efficacy rate against Fasciola spp. in clinical settings, significantly reducing fecal egg counts within a week post-treatment .
• Haemonchus spp. : In studies comparing various anthelmintics, this compound demonstrated superior effectiveness against Haemonchus spp., outperforming other treatments like levamisole and fenbendazole .

Pharmacokinetics and Bioavailability

The pharmacokinetic profile of this compound has been extensively studied to optimize its use in livestock. Key findings include:

• High Plasma Protein Binding : this compound exhibits a high degree of plasma protein binding (approximately 99%), contributing to its prolonged action in the body .
• Bioequivalence Studies : Research has confirmed that different formulations of this compound show similar pharmacokinetic parameters, ensuring consistent therapeutic outcomes across formulations .

Table 1: Pharmacokinetic Parameters of this compound

Clinical Studies and Milk Production

A randomized controlled trial evaluated the impact of this compound on milk production in dairy cattle. The study found that administering this compound improved milk yield and reduced antibody levels against Fasciola hepatica in milk samples .

Study Design Overview

• Population : First-calf heifers.
• Dosage : 0.2 ml/kg body weight.
• Duration : Administered at dry-off, between 80 and 42 days before calving.

Novel Applications in Oncology

Recent research indicates potential applications of this compound beyond veterinary medicine. It has been identified as a BRAFV600E enzyme inhibitor, suggesting its potential use in preparing drugs for treating certain tumors, including melanoma and colorectal cancer .

Conclusion and Future Directions

This compound remains a vital compound in veterinary medicine with proven efficacy against various parasitic infections in livestock. Its pharmacokinetic properties support its long-term use, while emerging research suggests novel applications in oncology. Future studies should focus on expanding its therapeutic uses and understanding its mechanisms further.

Closantel exerts its antiparasitic effects by uncoupling oxidative phosphorylation in the mitochondria of parasites, which disrupts the production of adenosine triphosphate (ATP), the cellular "fuel" . This mechanism leads to the accumulation of fumarate and ultimately results in the parasite’s demise . This compound also inhibits fumarate reductase, an essential enzyme involved in fumarate synthesis .

Closantel is unique among antiparasitic agents due to its specific mechanism of action and broad-spectrum activity against various parasites. Similar compounds include other salicylanilide derivatives such as oxyclozanide and rafoxanide . These compounds share similar chemical structures and mechanisms of action but may differ in their spectrum of activity and efficacy against specific parasites .

Closantel is an anthelmintic compound primarily used in veterinary medicine for the treatment of parasitic infections, particularly those caused by trematodes and nematodes. Recent studies have expanded its application to include antibacterial properties, showcasing its potential in combating multidrug-resistant bacterial infections. This article explores the biological activity of this compound, focusing on its antimicrobial effects, toxicity, and pharmacokinetics.

Antimicrobial Activity

This compound has demonstrated significant antibacterial activity, particularly against gram-negative bacteria. A study highlighted the synergistic effects of this compound when combined with polymyxin B against Acinetobacter baumannii, a notorious multidrug-resistant pathogen. The combination therapy was effective in inhibiting the development of resistance to polymyxin B, suggesting that this compound can serve as a valuable adjuvant in treating severe bacterial infections.

Key Findings:

• Minimum Inhibitory Concentration (MIC) : this compound alone showed MIC values greater than 128 mg/L against most A. baumannii isolates but achieved lower MICs (0.5 mg/L) against certain polymyxin-resistant strains when used in combination with polymyxin B .
• Synergistic Effects : The combination of polymyxin B (2 mg/L) with this compound (4-16 mg/L) effectively inhibited bacterial growth and prevented the emergence of resistance .

Case Studies on Toxicity

Despite its therapeutic benefits, this compound has been associated with adverse effects, particularly ocular toxicity. A notable case involved a 20-year-old female patient who experienced reversible blindness after receiving an incorrect prescription of this compound instead of triclabendazole for Fasciola hepatica infection. The patient's vision impairment was linked to retinal damage caused by the drug.

Case Highlights:

• Symptoms : The patient reported bilateral blurred vision and color blindness after taking this compound for three days.
• Treatment : Plasma exchange and high-dose corticosteroids were administered, resulting in partial recovery of vision over a follow-up period .

Pharmacokinetics

This compound exhibits a long half-life and high plasma protein binding capacity, which influences its distribution and elimination from the body. Studies indicate that after oral administration, this compound's half-life ranges from 22.7 to 26.7 days, with approximately 80% of the administered dose excreted in feces within eight weeks .

Pharmacokinetic Data:

Basic Research Questions

Q. What are the primary molecular mechanisms underlying Closantel’s anthelmintic activity, and how can these be experimentally validated?

this compound acts as a proton ionophore, disrupting mitochondrial membrane potential in parasites by binding to the H+/K+-ATPase transporter . To validate this, researchers can:

• Use in vitro assays (e.g., fluorescence-based mitochondrial membrane potential assays in Haemonchus contortus L3 larvae).
• Compare dose-response curves between wild-type and ATPase-knockout parasite strains.
• Employ molecular docking simulations to confirm binding affinity to target proteins. Table 1 : Key assays for mechanistic studies

Q. How should researchers select appropriate in vivo models to evaluate this compound’s efficacy against resistant nematode strains?

• Prioritize naturally resistant isolates (e.g., Teladorsagia circumcincta from field surveys) over lab-induced strains to reflect real-world resistance patterns.
• Use FECRT (Fecal Egg Count Reduction Test) with controlled dosing in sheep or cattle, ensuring sample sizes ≥10 animals/group to account for host variability .
• Include pharmacokinetic monitoring to correlate plasma concentrations with efficacy.

Q. What standardized protocols exist for quantifying this compound residues in animal tissues, and how can cross-lab reproducibility be ensured?

• Follow HPLC-MS/MS protocols validated by the Codex Alimentarius Commission (CAC/GL 71-2009). Key steps:

Homogenize tissue samples in acetonitrile:water (80:20).

Use deuterated this compound as an internal standard.

Validate recovery rates (≥85%) across triplicate runs .

• Share raw chromatograms and calibration curves in supplementary materials to aid reproducibility .

Advanced Research Questions

Q. How can contradictory data on this compound’s efficacy in different host species (e.g., cattle vs. sheep) be systematically analyzed?

• Conduct a meta-analysis of existing studies, stratifying by:

• Host pharmacokinetics (e.g., plasma half-life differences: 14 days in cattle vs. 10 days in sheep).

• Parasite burden metrics (eggs per gram vs. adult worm counts).

  • Use mixed-effects models to account for variability in dosing regimens and resistance profiles .
    Table 2 : Species-specific PK parameters of this compound

  Species	Half-life (days)	Cₘₐₓ (μg/mL)	Reference
  Cattle	14.2	32.5
  Sheep	9.8	28.1

Q. What experimental strategies can resolve conflicting hypotheses about this compound’s role in inducing oxidative stress in parasites?

• Combine transcriptomic profiling (RNA-seq) of this compound-exposed parasites with ROS (reactive oxygen species) detection assays (e.g., DCFH-DA fluorescence).
• If ROS levels increase but antioxidant genes (e.g., sod-1, gst) are downregulated, this supports mitochondrial dysfunction as the primary mechanism over oxidative stress .
• Validate using gene knockout strains (e.g., sod-1 mutants) to isolate contributing pathways.

Q. How can researchers design studies to investigate this compound’s potential synergism with benzimidazoles while avoiding confounding variables?

• Use fractional inhibitory concentration (FIC) indices in in vitro larval development assays.
• Control for:

• Metabolism interactions (e.g., CYP450 enzyme inhibition by this compound).
• Differential absorption rates via co-administration with pharmacokinetic enhancers (e.g., cyclodextrins) .
  • Apply response surface methodology (RSM) to model dose-response surfaces and identify optimal ratios.

Q. Methodological and Ethical Considerations

Q. What statistical approaches are recommended for addressing high inter-individual variability in this compound pharmacokinetic studies?

• Use non-linear mixed-effects modeling (NONMEM) to partition variability into host (e.g., weight, age) and environmental (e.g., feed composition) factors .
• Report coefficients of variation (CV%) for key parameters (AUC, Cₘₐₓ) with 90% confidence intervals.

Q. How should researchers mitigate bias when interpreting this compound resistance data from field trials?

• Blind laboratory analysts to treatment groups during fecal egg counts.
• Include negative controls (untreated animals) and positive controls (known susceptible strains) in each assay batch .
• Disclose funding sources and conflicts of interest in compliance with ICMJE guidelines .

Q. Emerging Research Frontiers

Q. What methodologies are suited for investigating this compound’s off-target effects on host gut microbiota?

• Perform 16S rRNA sequencing on fecal samples pre- and post-treatment, using Qiime2 for differential abundance analysis.
• Correlative analysis: Link microbiota shifts (e.g., Bacteroidetes/Firmicutes ratio) with host metabolic markers (e.g., serum SCFA levels) .

Q. How can machine learning improve predictive models of this compound resistance evolution?

• Train random forest classifiers on genomic data (SNPs in Hco-acr-8 gene) and treatment histories from surveillance databases.
• Validate models using spatial cross-validation to account for regional resistance patterns .