Pyrantel

Synthetic Routes and Reaction Conditions: Pyrantel is synthesized through a series of chemical reactions involving pyrimidine derivatives. The synthesis typically involves the reaction of 1-methyl-2-(2-thienyl)vinyl-5,6-dihydro-4H-pyrimidine with various reagents under controlled conditions .

Industrial Production Methods: Industrial production of this compound often involves the use of high-performance liquid chromatography (HPLC) for the purification and analysis of the compound. The process includes the use of acetonitrile, acetic acid, water, and diethylamine as solvents and reagents .

Types of Reactions: Pyrantel undergoes various chemical reactions, including oxidation, reduction, and substitution reactions. These reactions are essential for modifying the compound’s structure and enhancing its efficacy .

Common Reagents and Conditions: Common reagents used in the reactions involving this compound include acetonitrile, acetic acid, water, and diethylamine. The reactions are typically carried out under controlled temperature and pressure conditions to ensure optimal yields .

Major Products Formed: The major products formed from the reactions involving this compound include its pamoate salt, which is used in various pharmaceutical formulations .

Clinical Applications

Pyrantel is primarily indicated for the treatment of:

• Ascariasis : Caused by Ascaris lumbricoides.
• Enterobiasis : Commonly known as pinworm infection caused by Enterobius vermicularis.
• Hookworm Infections : Particularly effective against Ancylostoma duodenale and Necator americanus.

The standard dosage for these infections is typically around 10 mg/kg for ascariasis and enterobiasis, while a 3-day treatment at the same daily dose is recommended for hookworms .

Efficacy Against Soil-Transmitted Helminths

Recent studies have demonstrated that this compound pamoate significantly reduces worm burden in cases of soil-transmitted helminths. For instance, a study showed a reduction in worm burden by 53-72% when administered post-exposure .

Post-Exposure Prophylaxis

This compound pamoate has been evaluated for its use as a post-exposure prophylactic treatment. Administering it immediately after potential exposure to larval infections can paralyze the larvae in the gastrointestinal tract, preventing them from entering systemic circulation .

Case Study 1: Efficacy in Pediatric Populations

A randomized controlled trial involving children in sub-Saharan Africa demonstrated that this compound was highly effective in treating ascariasis and enterobiasis, achieving cure rates exceeding 96% . The study highlighted its safety profile and minimal side effects, making it suitable for mass drug administration programs.

Case Study 2: Use in Veterinary Medicine

In veterinary applications, this compound tartrate has shown effectiveness against various parasitic infections in animals. Its hydrophilic nature allows systemic absorption, which is beneficial for treating infections that have entered circulation . However, this form is associated with higher toxicity risks in humans.

Conclusions

This compound remains a cornerstone in the treatment of intestinal helminth infections due to its efficacy and safety profile. Its unique mechanism of action allows it to effectively paralyze and expel parasites from the host's gastrointestinal tract. Ongoing research continues to explore its potential applications, particularly in preventive measures against parasitic infections.

Pyrantel acts as a depolarizing neuromuscular blocking agent, causing sudden contraction followed by paralysis of the helminths. This results in the worms losing their grip on the intestinal wall and being expelled from the body . The compound targets nicotinic cholinergic receptors in the worms, leading to persistent depolarization and spastic paralysis .

Structural and Functional Analogues: Oxantel and Morantel

Pyrantel shares structural homology with oxantel and morantel, all of which are tetrahydropyrimidines. Molecular docking studies reveal differences in binding affinities to nAChRs:

• This compound : Binds to Ace-ACR-16 receptors with −5.5 kcal/mol energy but shows poor affinity (+1.1 kcal/mol) for Nam-ACR-16 receptors .
• Oxantel : Higher affinity (−6.4 kcal/mol) for Ace-ACR-16 but ineffective against Nam-ACR-16 (+3.6 kcal/mol) .
• Morantel : Intermediate affinity (−5.7 kcal/mol for Ace-ACR-16) but variable efficacy across species .

Table 1: Binding Affinities of Tetrahydropyrimidines to nAChRs

Source: Molecular docking simulations

In Haemonchus contortus, ACR-26/27 receptors are highly sensitive to this compound, whereas morantel targets Hco-L-AChR2 . This receptor specificity explains this compound’s broader efficacy against gastrointestinal nematodes compared to morantel.

Comparison with Other Anthelmintic Classes

Benzimidazoles (BZs)

• Efficacy : BZs (e.g., albendazole) achieve >90% cure rates for hookworms, whereas this compound requires weight-based dosing and shows lower efficacy (39% reduction at 1 mg/kg) .
• Resistance : BZ resistance is widespread, but this compound resistance is emerging in Parascaris equorum and cyathostomins .

Macrocyclic Lactones (Ivermectin)

• Spectrum : Ivermectin targets glutamate-gated chloride channels, effective against arthropods and nematodes. This compound is nematode-specific .
• Resistance : Ivermectin resistance is documented in P. equorum, whereas this compound resistance is more common in cyathostomins .

Table 2: Efficacy of this compound vs. Major Anthelmintics

Formulation-Specific Efficacy

This compound Pamoate vs. Citrate/Tartrate

• Pamoate : Lower solubility prolongs intestinal retention, achieving 75% efficacy against this compound-resistant Oesophagostomum dentatum in pigs .
• Citrate : Rapid absorption reduces large intestine bioavailability (23% efficacy against resistant O. dentatum) .
• Tartrate : Used in equine feed additives but shows variable efficacy against cyathostomins (51–90% reduction) .

Table 3: Efficacy of this compound Salts in Different Hosts

Synergy and Resistance Mechanisms

• Synergy with Cry5B : A 3:1 ratio of Cry5B:this compound achieves 100% elimination of hookworms, overcoming this compound’s standalone limitations .
• Resistance: Genome-wide studies identify quantitative trait loci (QTLs) linked to this compound resistance in Cylicocyclus nassatus, involving nAChR subunit mutations . In contrast, BZ resistance arises from β-tubulin polymorphisms .

Pyrantel is a broad-spectrum anthelmintic agent primarily used for the treatment of various parasitic worm infections. Its biological activity is characterized by a unique mechanism of action, pharmacokinetics, and efficacy across different types of helminths, including nematodes and cestodes. This article synthesizes recent research findings, case studies, and data tables to provide a comprehensive overview of this compound's biological activity.

This compound acts as a depolarizing neuromuscular blocking agent in helminths. It promotes the release of acetylcholine and inhibits cholinesterase, leading to extensive depolarization of the muscle membrane in parasites. This action results in paralysis and detachment from the host's intestinal walls, facilitating the expulsion of the parasites through normal peristalsis . Unlike other anthelmintics such as piperazine, which induce hyperpolarization and relaxation of muscle, this compound's mechanism leads to spastic paralysis .

Pharmacokinetics

• Absorption : this compound is poorly absorbed from the gastrointestinal tract, which allows it to act locally on intestinal parasites. Peak serum concentrations occur 1–3 hours after administration .
• Volume of Distribution : The drug has a limited volume of distribution due to its poor absorption and high local concentration at the site of action.

Case Study: Efficacy Against Pinworms

A study conducted by Kobayashi et al. (2020) evaluated the effectiveness of this compound Pamoate in eliminating pinworms. The study involved administering various concentrations of this compound in a medicated gel diet to Dubia roaches and measuring fecal worm ova counts over time.

Table 1: Fecal Worm Ova Counts Post-Treatment

The results indicated significant reductions in fecal ova counts across all treated groups compared to the control group, with Group D (26 mg/g) showing the most pronounced effects .

Post-Exposure Prophylaxis Study

Another study assessed this compound Pamoate's effectiveness as a post-exposure prophylactic treatment against Angiostrongylus cantonensis. The results showed that treatment significantly reduced worm burden by 53% to 72% when administered shortly after exposure .

Table 2: Worm Recovery Data

The data indicated a significant difference between control and treatment groups, confirming this compound's efficacy when administered immediately post-infection .

Comparative Efficacy Against Other Helminths

This compound has been shown to be effective against various helminths beyond pinworms:

• Dipylidium caninum : A study demonstrated that this compound-Oxantel induced significant mortality and reduced tegument thickness in D. caninum, confirming its therapeutic potential against tapeworms .
• Caenorhabditis elegans : Early studies reported up to 98% reduction in motility in adult nematodes following treatment with this compound Pamoate, showcasing its broad-spectrum efficacy against nematodes .

Basic Research Questions

Q. What experimental models are most appropriate for studying Pyrantel’s anthelmintic efficacy, and how should they be validated?

• Methodological Guidance : Use Caenorhabditis elegans or Heligmosomoides bakeri (nematode models) to assess paralysis and egg-hatching inhibition. Validate models by correlating in vitro LC50/EC50 values with in vivo fecal egg count reduction (FECR) in host organisms (e.g., rodents). Include negative controls (e.g., untreated worms) and positive controls (e.g., albendazole) to ensure assay specificity .

Q. How can researchers differentiate this compound’s neuromuscular action from other nicotinic agonists in in vitro assays?

• Methodological Guidance : Perform electrophysiological recordings (e.g., patch-clamp) on isolated parasite muscle cells to measure acetylcholine receptor (AChR) depolarization. Compare this compound’s dose-response curves with levamisole or nicotine, and use receptor antagonists (e.g., mecamylamine) to confirm target specificity. Statistical analysis should include ANOVA with post-hoc tests to assess significance .

Q. What are the critical parameters for designing dose-response studies in rodent models?

• Methodological Guidance : Use a minimum of 5 dose levels (e.g., 1–100 mg/kg) with sample sizes ≥10 animals per group. Measure FECR, worm burden reduction, and histopathological changes in intestinal tissues. Apply nonlinear regression models (e.g., log-dose vs. response) to calculate ED50 and 95% confidence intervals .

Advanced Research Questions

Q. How can conflicting data on this compound resistance in Ascaris spp. be systematically analyzed?

• Methodological Guidance : Conduct genomic sequencing of parasite populations to identify mutations in AChR subunits (e.g., acr-8, acr-26). Pair this with in vitro larval development assays under this compound exposure. Use multivariate regression to correlate genetic markers with phenotypic resistance thresholds (e.g., LC50 shifts ≥5x) .

Q. What experimental frameworks are optimal for studying this compound’s synergism with benzimidazoles?

• Methodological Guidance : Apply the Chou-Talalay combination index (CI) method in in vitro assays. Test fixed-ratio combinations (e.g., 1:1, 1:3 this compound:albendazole) and quantify synergism via CI <1. Validate findings in co-infected rodent models using isobolographic analysis .

Q. How can pharmacokinetic variability in pediatric vs. adult populations be addressed in this compound studies?

• Methodological Guidance : Use population pharmacokinetic (PopPK) modeling with covariates (e.g., body weight, hepatic function). Collect serial plasma samples post-administration and analyze via HPLC-MS. Apply Monte Carlo simulations to predict exposure differences and optimize dosing regimens .

Q. Data Analysis and Contradiction Resolution

Q. What statistical approaches resolve discrepancies in this compound’s efficacy across geographically distinct parasite isolates?

• Methodological Guidance : Perform meta-analysis of FECR data using random-effects models to account for heterogeneity. Stratify by isolate origin, host species, and diagnostic methods (e.g., Kato-Katz vs. PCR). Sensitivity analysis should exclude outliers and low-quality studies (e.g., sample size <50) .

Q. How should researchers validate conflicting in silico predictions of this compound-receptor binding?

• Methodological Guidance : Compare molecular docking results (e.g., AutoDock Vina) with site-directed mutagenesis data. Use cryo-EM structures of AChR-Pyrantel complexes to validate binding poses. Discrepancies require re-evaluation of force field parameters or solvent models in simulations .

Q. Tables for Key Methodological Comparisons