Diethylcarbamazine

Synthetic Routes and Reaction Conditions: Diethylcarbamazine is synthesized from 4-methylpiperazine. The synthesis involves the reaction of 4-methylpiperazine with diethylcarbamoyl chloride under controlled conditions to form this compound .

Industrial Production Methods: In industrial settings, this compound is produced by reacting 4-methylpiperazine with diethylcarbamoyl chloride in the presence of a suitable solvent and catalyst. The reaction is typically carried out at elevated temperatures to ensure complete conversion of the reactants to the desired product .

Types of Reactions: Diethylcarbamazine undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized to form this compound-N-oxide.

Reduction: Reduction reactions can convert this compound to its corresponding amine derivatives.

Substitution: this compound can undergo substitution reactions with various electrophiles to form substituted derivatives.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents such as hydrogen peroxide or peracids are used under mild conditions.

Reduction: Reducing agents like lithium aluminum hydride or sodium borohydride are employed under controlled conditions.

Substitution: Electrophiles such as alkyl halides or acyl chlorides are used in the presence of a base to facilitate substitution reactions.

Major Products Formed:

Oxidation: this compound-N-oxide.

Reduction: Amine derivatives of this compound.

Substitution: Substituted this compound derivatives.

Diethylcarbamazine (DEC) is a synthetic anthelmintic drug used to treat filarial diseases, including tropical pulmonary eosinophilia, loiasis, and lymphatic filariasis . It is highly specific for several parasites and lacks toxic metallic elements .

Scientific Research Applications

Treatment of Lymphatic Filariasis: DEC is a drug of choice for treating lymphatic filariasis (LF), used alone or in combination as a mass drug administration (MDA) preventive strategy . Studies have shown that repeated rounds of MDA with DEC and albendazole can significantly reduce filariasis infection rates .

• Three rounds of MDA decreased microfilaremia rates by 94% .
• Filarial antigenemia rates decreased by 64% after three rounds of MDA .
• Combining DEC with albendazole in mass treatment programs shows greater activity against adult worms . A study comparing DEC alone to DEC plus albendazole showed no statistically significant difference in decreasing microfilaria, but the combination resulted in a significant decrease in Og4C3 antigen prevalence .
• Combining Ivermectin, this compound Citrate, and Albendazole improves control of multiple neglected tropical diseases .

Anti-inflammatory Properties: DEC possesses anti-inflammatory properties by interfering with arachidonic acid metabolism, involving lipoxygenase (LOX) and cyclooxygenase (COX) enzymes .

• DEC reduces lung injury, PMN migration, and the release of proinflammatory cytokines .
• It can be used as a potential anti-inflammatory drug for chronic hepatic inflammation .
• DEC has shown potential in reducing hepatic abnormalities caused by malnutrition and liver injuries in experimental alcoholism models .

Mechanism of Action: The mechanism of action of this compound is thought to involve sensitizing the microfilariae to phagocytosis .

• DEC's activity against Brugia malayi microfilariae depends on inducible nitric-oxide synthase and the cyclooxygenase pathway .
• DEC directly and rapidly paralyzes parasites by opening TRP channels in muscle .
• The opening of TRP channels produces contraction and subsequent activation of calcium-dependent SLO-1K channels .

Pharmacokinetics: After oral administration, this compound is readily absorbed . A population pharmacokinetics model found that body weight and gender were significant covariates for the volume of distribution of DEC .

Diethylcarbamazine exerts its effects by inhibiting arachidonic acid metabolism in microfilariae. This inhibition makes the microfilariae more susceptible to innate immune attack but does not kill the parasites outright . The compound sensitizes the microfilariae to phagocytosis, and its activity is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway . Additionally, this compound targets the cyclooxygenase pathway and COX-1 .

Comparative Analysis with Similar Compounds

DEC vs. Ivermectin

Efficacy :

• Both DEC and ivermectin rapidly reduce skin microfilariae in onchocerciasis. However, ivermectin maintains significantly lower microfilarial counts (vs. placebo) for up to six months post-treatment, whereas DEC’s effects diminish faster .
• In lymphatic filariasis, a single ivermectin dose (200–400 µg/kg) achieves microfilarial clearance comparable to DEC’s 12-day regimen .

Adult Worm Activity :

• Neither drug kills adult Onchocerca worms, but DEC shows partial efficacy against adult Wuchereria in combination therapies .

Key Data :

Sources:

DEC vs. Flubendazole

Efficacy :

• Flubendazole reduces microfilariae more slowly than DEC but achieves sustained suppression (100% at 12 months vs. DEC’s resurgence to baseline levels) .
• Flubendazole also demonstrates adulticidal activity against Onchocerca, which DEC lacks .

Key Data :

Sources:

DEC vs. Albendazole and Combination Therapies

DEC + Albendazole (DA) :

• DA reduces microfilariae by 60–70% but requires repeated dosing for lymphatic filariasis elimination .

Triple Therapy (Ivermectin + DEC + Albendazole, IDA) :

• IDA achieves >90% microfilarial clearance in one dose and eliminates lymphatic filariasis in two annual rounds, outperforming DA .
• IDA also reduces co-infections (e.g., hookworm) due to albendazole’s broad-spectrum activity .

Key Data :

Sources:

DEC vs. Montelukast/Levocetirizine (Allergic Rhinitis)

• DEC outperforms montelukast and levocetirizine in allergic rhinitis, with sustained symptom relief for 3 months post-treatment (vs. relapse in comparator groups) .
• DEC’s cost-effectiveness and lower sedation risk make it a promising alternative .

Emerging Comparators and Mechanisms

• GST Inducers : DEC upregulates glutathione S-transferase (GST) in filarial parasites, a mechanism shared with butylated hydroxyanisole. GST inhibitors (e.g., ethacrynic acid) show synergistic antifilarial effects .

Diethylcarbamazine (DEC) is a synthetic organic compound primarily used as an anthelmintic agent in the treatment of lymphatic filariasis and other parasitic infections. Its biological activity is characterized by a complex interplay between direct effects on parasites and modulation of host immune responses. This article delves into the mechanisms of action, pharmacokinetics, and clinical implications of DEC, supported by research findings and case studies.

The biological activity of DEC is multifaceted, involving both direct effects on parasites and indirect effects through the host's immune system.

Direct Effects on Parasites:

• Activation of TRP Channels: Recent studies have shown that DEC activates Transient Receptor Potential (TRP) channels, particularly TRP-2 in Brugia malayi muscle cells. This activation leads to rapid spastic paralysis of the parasites, which can last for several hours. The mechanism involves calcium-dependent channels that facilitate muscle contraction and subsequent paralysis .
• Impact on Arachidonic Acid Pathways: DEC also influences the arachidonic acid metabolic pathway, inhibiting cyclooxygenase (COX) enzymes and affecting nitric oxide synthase (iNOS) pathways. These interactions are crucial for its efficacy in vivo, as they enhance phagocytosis and increase microfilariae adherence to granulocytes .

Indirect Effects via Host Immune Modulation:
DEC sensitizes microfilariae to phagocytosis by enhancing immune responses. It has been observed that DEC administration leads to a significant drop in microfilariae counts within minutes, indicating a rapid immune response facilitated by host factors .

Pharmacokinetics

DEC is readily absorbed following oral administration, with bioavailability being a critical factor in its therapeutic effectiveness. The drug is typically administered in tablet form at doses of 50 mg or 100 mg. Its pharmacokinetic profile allows for effective treatment regimens in endemic regions where lymphatic filariasis is prevalent .

Clinical Applications

DEC has been employed in various clinical settings, particularly in mass drug administration (MDA) programs aimed at controlling lymphatic filariasis. It is often combined with other antiparasitic agents like albendazole or ivermectin to enhance efficacy and reduce transmission rates.

Case Studies

• Lymphatic Filariasis Control Programs: In regions where lymphatic filariasis is endemic, DEC has been used effectively in MDA campaigns. Studies indicate that such programs have led to significant reductions in infection rates and associated morbidity .
• Safety and Efficacy Trials: Clinical trials have demonstrated that DEC is generally well-tolerated, with side effects being mild and transient. Adverse reactions are typically associated with the inflammatory response to dying microfilariae rather than the drug itself .

Summary of Research Findings

The following table summarizes key findings from various studies regarding the biological activity of DEC:

Q. What validated analytical methods are recommended for quantifying diethylcarbamazine in pharmaceutical formulations and biological samples?

Basic
Reverse-phase high-performance liquid chromatography (RP-HPLC) is widely validated for quantifying this compound citrate in pharmaceutical formulations. The method demonstrates linearity in the range of 1–15 µg/ml with a regression equation of Y = 561,967x + 13,655 (r² = 0.999) and accuracy confirmed via recovery studies (98–102%) . For medicated salt in field settings, a low-cost titrimetric approach using back-titration with sodium hydroxide is recommended, achieving precision within ±5% .

Q. How can researchers resolve contradictions in this compound's mechanism of action between direct antiparasitic effects and host-mediated immune responses?

Advanced
To reconcile these mechanisms, employ in vitro electrophysiological assays (e.g., voltage-clamp on Ascaris suum muscle cells) to study DEC’s direct modulation of SLO-1 potassium channels . Concurrently, use in vivo models (e.g., rat AMI or filarial infection) to assess host immune modulation, such as DEC’s inhibition of NF-κB activation or prostaglandin synthesis . Cross-validate findings by combining DEC with immune modulators (e.g., emodepside) to observe synergistic effects .

Q. What are the key considerations when designing in vivo studies to evaluate this compound's cardioprotective effects?

Basic
Use male Wistar rats (n=6–12/group) with standardized weights (230–250 g) and housing conditions (23°C, 12h light/dark cycle). Include control groups (sham, DEC-alone), an AMI model group (isoproterenol-induced), and a treatment group (DEC 50 mg/kg/day for 12 days). Measure cardiac biomarkers (CK, LDH), oxidative stress markers (ROS), and inflammatory cytokines. Apply one-way ANOVA with Tukey’s post-hoc test for statistical analysis .

Q. What methodologies are employed to assess the synergistic effects of this compound with other anthelmintics like emodepside?

Advanced
Use voltage-clamp techniques to measure SLO-1 potassium current activation in Ascaris suum. DEC (100 µM) shifts the voltage sensitivity (V50) from 7.66 ± 0.6 mV to 6.26 ± 0.6 mV (p < 0.001), and combined with emodepside (1 µM), V50 decreases further to 3.16 ± 1.1 mV (p < 0.01) . Pair these in vitro results with in vivo efficacy trials in filarial models, monitoring microfilarial clearance rates and parasite paralysis .

Q. How do physiological factors such as urinary pH influence this compound's pharmacokinetics, and how should this be accounted for in study design?

Basic
Alkaline urine (pH 7.5–8) prolongs DEC’s elimination half-life, while acidification accelerates excretion. In pharmacokinetic studies, control dietary intake (e.g., vegetarian vs. non-vegetarian diets) and monitor urinary pH. Use crossover designs to compare DEC clearance under varying pH conditions .

Q. What strategies can be implemented in clinical trial designs to evaluate the safety and efficacy of this compound in community-based mass drug administration programs?

Advanced
Adopt cluster randomization and collect data via tablet-based systems for real-time uploads. Include endpoints like filarial antigen test (FTS) scores, microfilarial (MF) prevalence, and adverse event rates. For example, in DA (DEC + albendazole) vs. IDA (ivermectin + DEC + albendazole) trials, MF prevalence in FTS-positive individuals decreased from 40% to 7.3% post-treatment .

Q. What statistical approaches are recommended for analyzing data from studies comparing this compound's efficacy across different treatment groups?

Basic
Use one-way ANOVA for inter-group comparisons (e.g., cardiac biomarkers in AMI models) followed by Tukey’s test for pairwise analysis. For non-normal data, apply Kruskal-Wallis with Dunn’s correction. Report mean ± SD and significance thresholds (p < 0.05) .

Q. How can researchers investigate the role of this compound in modulating oxidative stress and inflammatory pathways in parasitic infections?

Advanced
Quantify ROS production via fluorescence assays (e.g., DCFH-DA) in AMI models, where DEC reduces ROS by 50% (p < 0.01) . Measure NF-κB activation using Western blotting and cytokine levels (e.g., TNF-α, IL-6) via ELISA. Co-administer DEC with prostaglandin inhibitors (e.g., indomethacin) to explore feedback mechanisms .

Q. What experimental models are used to predict and counteract potential anthelmintic resistance to this compound?

Advanced
Develop in vitro resistance models by exposing parasites (e.g., Brugia malayi) to sublethal DEC doses over multiple generations. Use genetic sequencing to identify resistance markers (e.g., SLO-1 mutations). Test DEC in combination with emodepside or albendazole to delay resistance, leveraging synergistic pathways .

Q. How should researchers address variability in DEC efficacy across different filarial species (e.g., Wuchereria bancrofti vs. Loa loa)?

Advanced
Conduct species-specific in vitro microfilarial motility assays and compare DEC’s IC50 values. In clinical trials, stratify participants by infection type and monitor antigen clearance kinetics. For example, DEC achieves >90% microfilarial reduction in W. bancrofti but requires caution in Loa loa-endemic areas due to encephalopathy risks .