Diethylcarbamazine

Arachidonic Acid Metabolism Inhibition in Microfilariae

This compound acts as an inhibitor of arachidonic acid metabolism in microfilariae. wikipedia.orgnih.gov This interference is thought to make the microfilariae more susceptible to attack by the host's innate immune system, although it does not necessarily kill the parasites directly. wikipedia.org Studies have confirmed the important role of the arachidonic acid metabolic pathway in this compound's in vivo mechanism of action. drugbank.comhmdb.caresearchgate.netdrugbank.com

This compound affects the 5-lipoxygenase pathway. drugbank.comresearchgate.netdrugbank.com Research indicates that this compound can interrupt this pathway distal to the formation of 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) from arachidonic acid by 5-lipoxygenase. oup.com This interference contributes to the reduction in the production of certain eicosanoids. capes.gov.br

In addition to its effects on the 5-lipoxygenase pathway, this compound also targets the cyclooxygenase pathway and specifically COX-1. drugbank.comhmdb.caresearchgate.netdrugbank.comnih.gov Studies have shown that this compound's activity against Brugia malayi microfilariae is dependent on the cyclooxygenase pathway. drugbank.commedex.com.bdhmdb.caresearchgate.netdrugbank.comnih.gov Furthermore, experiments have demonstrated that treatment with this compound can result in a reduction in the amount of COX-1 protein in peritoneal exudate cells. researchgate.netnih.gov

This compound interferes with both cyclooxygenase and lipoxygenase pathways, leading to a reduction in the production of various eicosanoids, including thromboxane, prostacyclin, prostaglandins, and leukotrienes. capes.gov.brresearchgate.netwikem.orgnih.gov This reduction in inflammatory mediators is considered part of its anti-inflammatory properties. researchgate.netnih.gov Studies have shown that this compound can decrease the release of prostacyclin, prostaglandin E2, and thromboxane B2 from endothelial monolayers. nih.gov

Data from in vitro studies on bovine pulmonary arterial endothelium monolayers exposed to 2.5 µM this compound showed significant reductions in the release of cyclooxygenase pathway products:

These findings suggest that the effects of this compound on host endothelial and parasite eicosanoid production may contribute to its mechanism of lowering microfilariae levels in circulation. nih.gov

Cyclooxygenase Pathway and COX-1

Direct Effects on Nematode Parasites

While initially thought to act primarily through host-mediated effects, recent studies have demonstrated that this compound also exerts direct effects on nematode parasites. researchgate.netnih.govnih.govproquest.comcambridge.org These direct effects contribute to the inhibition of parasite motility. researchgate.net

Low concentrations of this compound have been shown to have a direct effect on Brugia malayi parasites by opening Transient Receptor Potential (TRP) channels. researchgate.netnih.govasm.orgnih.govresearchgate.netresearchgate.netaminer.cnresearchgate.net This activation of TRP channels promotes calcium entry into the parasite muscle cells. asm.orgresearchgate.netresearchgate.net The influx of calcium can subsequently activate calcium-dependent SLOw poke potassium channels (SLO-1), which are the putative targets of other anthelmintics like emodepside. nih.govasm.orgnih.govresearchgate.netresearchgate.net The opening of these channels in somatic muscle cells can lead to a temporary spastic paralysis of the parasite. researchgate.netnih.gov Specifically, this compound has been shown to interact with the TRPC ortholog receptor TRP-2 to facilitate calcium entry into Brugia muscle cells. asm.orgresearchgate.netresearchgate.net

Studies investigating the effects of this compound on single Brugia muscle cells using calcium-imaging techniques have provided evidence for this mechanism. asm.orgresearchgate.net The direct effect of this compound on opening TRP channels, including TRP-2, is proposed as a mechanism for the rapid onset of its action. nih.gov

The synergistic action observed when this compound is combined with emodepside on nematode motility and muscle membrane potentials may be explained by the combined effects on SLO-1 K⁺ channels, involving this compound's effects on arachidonic acid and nitric oxide pathways in the parasite, as well as emodepside's direct effects on SLO-1 K⁺ channels. nih.gov

Activation of Calcium-Dependent SLOw poke Potassium Channels (SLO-1)

Recent studies have revealed a direct effect of this compound on filarial parasites, specifically involving the activation of Transient Receptor Potential (TRP) channels in the parasite's muscle cells. nih.govnih.govresearchgate.netasm.org This activation, particularly of the TRPC ortholog TRP-2, promotes the entry of calcium ions into the muscle cells. nih.govnih.govresearchgate.netasm.orgresearchgate.net The increased intracellular calcium concentration, in turn, activates calcium-dependent SLOw poke potassium channels (SLO-1). nih.govnih.govresearchgate.netasm.orgresearchgate.netjensenlab.org Activation of SLO-1 potassium channels leads to hyperpolarization of the muscle cell membrane, reducing muscle excitability and resulting in temporary spastic paralysis of the parasite. patsnap.comnih.govresearchgate.netjensenlab.orgpfizer.com This direct action on ion channels contributes to the rapid onset of DEC's effects observed in vivo. nih.gov

Impact on Parasite Motility and Viability

This compound has been shown to directly inhibit the motility of both microfilariae and adult filarial worms. nih.govafricaresearchconnects.com Studies on Onchocerca volvulus microfilariae, for instance, demonstrated a concentration-dependent decrease in motility and survival when exposed to DEC in vitro. africaresearchconnects.com The initial effect observed was a reduction in motility, followed by death associated with a loss of darkly refractile nuclei. africaresearchconnects.com This suggests that DEC has both an immobilizing and a lethal action on microfilariae at concentrations achievable during treatment. africaresearchconnects.com While some studies historically suggested DEC primarily acted via the host immune system, recent findings confirm a direct inhibitory effect on parasite motility. nih.govafricaresearchconnects.com

Disruption of Adult Worm Muscular Activity

In addition to its effects on microfilariae, this compound has been observed to affect the muscular activity of adult filarial worms. patsnap.com This disruption can lead to paralysis and ultimately the death of the parasites. patsnap.com Although the mode of action on adult worms is less extensively documented than on microfilariae, there is evidence suggesting that DEC is macrofilaricidal, with degenerating adult worms observed in lymph nodes post-treatment. nafdac.gov.ngwho.int However, the macrofilaricidal effects can be inconsistent. nafdac.gov.ngwho.int The activation of TRP and SLO-1 channels discussed earlier is also relevant to the disruption of adult worm muscle function, contributing to paralysis. nih.govnih.govresearchgate.netasm.org

Impact on Reproductive Capabilities of Female Worms

This compound also impacts the reproductive capabilities of female filarial worms, contributing to a reduction in microfilarial loads. patsnap.com Studies have shown that DEC can reduce the total number of intrauterine embryos, particularly ova, indicating an inhibition of early embryogenesis. kln.ac.lk By limiting the production and release of microfilariae from female worms, DEC indirectly reduces the transmission potential of the parasite. patsnap.com

Sensitization of Microfilariae to Phagocytosis

A primary host-mediated mechanism involves the sensitization of microfilariae to phagocytosis by host immune cells. drugbank.comannapurnapharmacy.compatsnap.comCurrent time information in Zagorje ob Savi, SI.nih.gov this compound is thought to alter the surface properties of microfilariae, making them more recognizable and susceptible to uptake and destruction by phagocytes, such as macrophages and granulocytes. patsnap.comnafdac.gov.ngcambridge.org This process is believed to involve changes in the parasite's arachidonic acid metabolism, which can lead to amplified endothelial adhesion and enhanced adherence of host platelets and granulocytes to the microfilariae. nafdac.gov.ngwho.intcambridge.org The rapid sequestration of microfilariae in organs like the liver and spleen, where they are subsequently phagocytosed, is a hallmark of DEC treatment. jsparasitol.org Inducible nitric oxide synthase (iNOS) and nitric oxide have been shown to be essential for this rapid sequestration. drugbank.comnafdac.gov.ngwho.intplos.org

Alteration of Host Arachidonic Acid Metabolism

Host arachidonic acid metabolism plays a crucial role in inflammatory responses, leading to the production of various lipid mediators, including prostaglandins and leukotrienes. This compound has been shown to interfere with this pathway, contributing to its anti-inflammatory properties and its effects on parasite clearance. wikipedia.orgwikipedia.orgnih.gov

Inhibition of Lipoxygenase (LOX) and Cyclooxygenase (COX) Enzymes

Studies have demonstrated that DEC interferes with both the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, which are central to the metabolism of arachidonic acid. wikipedia.orgwikipedia.orgnih.govuwm.edu.pl This interference leads to a reduction in the production of various eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes. wikipedia.orguwm.edu.pl Specifically, DEC has been identified as an inhibitor of enzymes in the 5-lipoxygenase pathway. wikipedia.org Experimental evidence supports the interaction of DEC with the host cyclooxygenase pathway for prostaglandin synthesis. wikipedia.org

Reduction of Prostaglandin D2 (PGD2) Production

The inhibition of COX and LOX enzymes by this compound results in the suppression of prostaglandin production, including Prostaglandin D2 (PGD2). wikipedia.orguni.lu PGD2 is a major prostaglandin produced by mast cells and is involved in various physiological and pathological processes, including inflammation and allergic responses. wikipedia.orgctdbase.org Reduced production of PGD2 due to DEC's action on arachidonic acid metabolism can influence immune cell responses. uni.lu

Modulation of Nitric Oxide Pathways

This compound's activity is also linked to the modulation of host nitric oxide pathways. Nitric oxide (NO) is a signaling molecule involved in numerous physiological processes, including immune responses and vasodilation. wikipedia.orgctdbase.orgiiab.meguidetopharmacology.org

Dependence on Inducible Nitric Oxide Synthase (iNOS)

Research indicates that the efficacy of this compound, particularly its activity against microfilariae, is dependent on host inducible nitric oxide synthase (iNOS) and nitric oxide. wikipedia.orgiiab.mefishersci.canih.govitb.ac.iduni.lu Studies using iNOS knockout mice have shown that DEC's activity against Brugia malayi microfilariae is abolished in the absence of iNOS, suggesting a critical role for this enzyme in the drug's mechanism of action. wikipedia.orgfishersci.canih.govuni.lu Inducible nitric oxide synthase produces large amounts of NO as a defense mechanism and is synthesized by various cell types in response to cytokines. wikipedia.org

Inhibition of Nuclear Transcription Factor Kappa B (NF-κB) Activation

Recent studies have indicated that this compound inhibits the activation of nuclear transcription factor Kappa B (NF-κB). wikipedia.orguwm.edu.pl NF-κB is a key regulator of genes involved in inflammatory and immune responses. wikipedia.orgyoutube.com

Impact on Leukocyte Chemotaxis and Granulocyte Degranulation

This compound has been shown to block several steps in both the cyclooxygenase and lipoxygenase pathways, which are involved in the production of inflammatory mediators. This interference includes the inhibition of leukocyte chemotaxis and granulocyte degranulation axonmedchem.comresearchgate.net. By affecting these processes, DEC can modulate the recruitment and activation of immune cells at the site of infection or inflammation. Studies suggest that DEC's influence on arachidonic acid metabolism contributes to its anti-inflammatory properties researchgate.net.

Enhancement of Platelet and Granulocyte Adhesion and Cytotoxic Activity

Evidence suggests that this compound enhances the adherence and cytotoxic activity of host platelets and granulocytes, particularly towards microfilariae researchgate.netnih.govcambridge.orgcolab.ws. This effect is thought to be mediated, in part, by the drug's alteration of arachidonic acid metabolism in both the microfilariae and host endothelial cells nih.govcambridge.org. The resulting changes can lead to amplified endothelial adhesion, contributing to the immobilization of microfilarial parasites nih.govcambridge.org. Enhanced adherence of human neutrophils and eosinophils to tissue culture plastic after incubation with this compound citrate has been observed, with eosinophils showing greater sensitivity researchgate.net. This direct stimulation of host effector cell adherence may partially explain DEC's therapeutic action in vivo researchgate.net. This enhancement of adherence and cytotoxicity by host platelets and granulocytes represents an activation of the innate, non-specific immune system nih.govcambridge.org.

Influence on Eosinophilopoiesis and Eosinophil Accumulation

Research findings related to DEC's influence on eosinophils are summarized in the table below:

Enhancement of Antibody Production and Cytokine Response

This compound has been reported to have immunomodulatory properties, including the enhancement of antibody production and cytokine responses tandfonline.comnih.govnih.gov. Studies in mice challenged with antigens have shown that DEC treatment can enhance cytokine production and antibody production tandfonline.comnih.govnih.gov. Specifically, low-dose DEC treatment enhanced cytokine production in response to a thymus-dependent antigen (tetanus toxoid) and antibody production in response to a thymus-independent antigen (lipopolysaccharide) tandfonline.comnih.gov. These effects suggest a stimulating immunomodulatory role for DEC, influencing both cellular and humoral immune responses tandfonline.comnih.gov. The enhancement of antibody production and cytokine response may contribute to the host's ability to clear parasites nih.gov.

Influence of Body Weight and Gender

Body weight and gender have been identified as significant covariates influencing the pharmacokinetics of this compound, particularly affecting the volume of distribution (V/F). researchgate.netnih.govnih.govresearchgate.netasm.org Population pharmacokinetic modeling has indicated that body weight significantly impacts drug exposure in both male and female populations. nih.govresearchgate.netasm.org One study observed a correlation between body weight and gender over the volume of distribution. researchgate.netnih.gov Model-based simulations have demonstrated that body weight and sex affect drug exposure parameters, including Cmax and AUC. unmc.edu While DEC dosing is often dependent on body weight, intersubject variations in pharmacokinetic parameters could be related to the degree of dose adjustment based on weight. researchgate.netnih.gov The Cmax for DEC was found to be higher in female participants compared to male participants in one study. nih.govplos.org

Impact of Infection Status

Studies have investigated the impact of infection status on this compound pharmacokinetics. In an open-label cohort study involving adults infected with Wuchereria bancrofti and uninfected individuals, moderate to heavy W. bancrofti infection did not significantly affect the pharmacokinetic parameters for DEC following a single co-administered dose with albendazole and ivermectin, compared to uninfected individuals. researchgate.netplos.orgresearchgate.net There was no significant difference in AUC0-inf or Cmax between LF-infected and uninfected participants. plos.orgresearchgate.net The inclusion of infection status as a covariate in population pharmacokinetic models did not appear to improve data fitting in one study. nih.gov

Microfilaricidal Efficacy

DEC is recognized as an effective microfilaricidal agent against the lymphatic-dwelling filariae. oup.comnih.gov Studies have consistently shown that DEC treatment leads to substantial reductions in the prevalence and density of microfilariae (mf) in the blood. nih.govnih.govoup.com For instance, mass treatment with DEC-medicated salt has resulted in large reductions in microfilariae prevalence, ranging from 43% to 100%, in studies with high coverage levels. nih.gov Significant decreases in microfilariae density have also been observed. nih.gov A study using DEC-medicated salt for one year reported a 99.5% reduction in mf density. nih.gov Another study in Haiti showed a 95% reduction in mf prevalence after one year of treatment. nih.gov

Adulticidal Efficacy

While primarily known for its microfilaricidal effects, research indicates that DEC can also damage or kill adult filarial worms, although this effect can be inconsistent. jst.go.jpoup.comnih.govijdvl.comwho.int Studies suggest that conventional dosages of DEC can effectively kill adult worms in many patients infected with W. bancrofti, B. malayi, and B. timori. oup.comnih.gov Ultrasonography studies have shown that even single doses of DEC can kill adult worms when they are susceptible. ijdvl.comoup.com However, a significant proportion of adult W. bancrofti may not be susceptible to DEC. oup.com Histological evidence also supports an adulticidal effect of low-dose DEC in bancroftian filariasis. oup.com

Impact on Disease Transmission

The sustained reduction of microfilariae levels by DEC is crucial for preventing the transmission of lymphatic filariasis. ijdvl.com By significantly decreasing the number of circulating microfilariae, which are the stage transmitted by mosquitoes, DEC treatment helps to interrupt the parasite's life cycle. nih.govnih.gov Studies have shown that mass administration of DEC can lead to substantial reductions in vector infection and infectivity rates. nih.govoup.comnih.gov For example, ten rounds of mass DEC administration in south India resulted in a 91% reduction in vector infection rates and an 89% reduction in vector infectivity rates. oup.comnih.gov These reductions in microfilaremia and vector infection contribute significantly to the interruption of transmission. nih.govoup.com

Effectiveness of Single-Dose Regimens

Single-dose regimens of DEC have been investigated for their effectiveness, particularly in mass drug administration (MDA) programs. jst.go.jpnih.govwho.intresearchgate.netnih.gov Studies have indicated that a single dose of DEC can be as effective as multi-dose regimens in clearing microfilariae from the blood. ijdvl.comwho.int Annual single-dose treatments with DEC have been reported to be effective in reducing microfilariae rate and density, making them applicable for large-scale control campaigns. researchgate.net Research in Brazil demonstrated a marked reduction in mf, circulating filarial antigen (CFA), and antifilarial antibodies in individuals infected with W. bancrofti after repeated rounds of annual single-dose DEC. nih.gov A meta-analysis across studies also suggested that a single dose is as effective as a 12-day treatment regimen for microfilariae clearance. who.int

Efficacy of Spaced-Dose and Low-Dose Regimens

Spaced-dose and low-dose DEC regimens have also been explored for their efficacy. jst.go.jpoup.com Studies suggest that spaced doses of DEC (weekly or monthly) may be more effective than the same total dosage given in consecutive daily doses for killing adult worms. oup.comnih.gov Chronic administration of low-dose DEC, such as through medicated salt, has been shown to effectively control filariasis caused by W. bancrofti or B. malayi. oup.comnih.govnih.gov This approach has demonstrated large and consistent reductions in microfilariae prevalence and density in endemic communities. nih.gov

Combination Chemotherapy Studies

Combination chemotherapy involving DEC and other antifilarial drugs has been a significant area of research to enhance efficacy and accelerate elimination efforts. jst.go.jpoup.comoup.comajtmh.orgnih.govoup.comwustl.edumdpi.comrjpbr.complos.orgmedrxiv.orgplos.orgplos.orgwustl.eduoup.comnih.gov Combinations of DEC with albendazole (ALB) or ivermectin (IVM), or a triple combination of IVM, DEC, and ALB (IDA), have been studied. jst.go.jpoup.comoup.comajtmh.orgnih.govoup.comwustl.edumdpi.comrjpbr.complos.orgmedrxiv.orgplos.orgplos.orgwustl.eduoup.comnih.gov

Studies have indicated that drug combinations containing DEC are highly effective against microfilarial prevalence and intensity compared to single drugs or other combinations. nih.gov Combined treatment with DEC plus ALB has shown significant reductions in microfilarial intensity. nih.gov

More recently, the triple-drug combination (IDA) has demonstrated superior efficacy in clearing microfilariae compared to the two-drug regimen of DEC and ALB. ajtmh.orgoup.comwustl.eduplos.orgmedrxiv.orgplos.orgplos.orgoup.comnih.gov Clinical trials have shown that a single dose of IDA is significantly more effective for clearing W. bancrofti blood microfilariae than single or two annual doses of DEC/ALB. nih.gov For example, one study reported that 96% of participants treated with IDA were amicrofilaremic at 24 months, compared to 56% after a single dose of DEC/ALB and 75% after two annual doses of DEC/ALB. nih.gov Another study showed that one year after a single round of MDA, IDA cleared microfilariae in 96.3% of infected participants, compared to 83.6% in the DA arm. plos.org In Haiti, MDA with IDA was significantly more effective for clearing microfilariae compared to the standard DA regimen. plos.org

While IDA shows enhanced microfilaricidal efficacy, the impact on clearing filarial antigenemia (suggesting adult worm burden) can be less pronounced and similar between combination regimens. plos.orgplos.orgwustl.edunih.gov

Here is a summary of some research findings on the efficacy of DEC-containing regimens:

This compound with Albendazole

The combination of this compound and albendazole has been a widely used two-drug regimen for mass drug administration (MDA) programs aimed at eliminating lymphatic filariasis (LF). Clinical trials have investigated the efficacy of this combination in clearing microfilariae (Mf) from the blood of infected individuals. Studies have shown that while effective, this dual therapy may not achieve the same sustained clearance rates as newer triple-drug regimens in some settings. For instance, clinical trials in Papua New Guinea (PNG) demonstrated that a single dose of the triple-drug combination (IDA) was more effective than the DEC plus albendazole (DA) combination for achieving sustained clearance of Wuchereria bancrofti Mf. oup.com In a study in Côte d'Ivoire, IDA was more effective for clearing W. bancrofti Mf and killing adult worms than ivermectin plus albendazole (IA), but the Mf clearance effect was not as long-lasting as seen in studies in PNG or Indonesia. oup.com However, a single treatment with IDA was found to be equivalent to two annual treatments with IA in that setting. oup.com

A community-based cluster-randomized trial in a moderately endemic, treatment-naive area in PNG compared the safety and efficacy of IDA and DA for LF. The study found that IDA was more effective for clearing microfilariae compared to DA. plos.org Similarly, a study in Haiti showed that significantly more participants who were Mf positive at baseline became Mf negative one year after treatment with IDA (94.4%) compared to after DA (75.9%). plos.org

Triple-Drug Therapy (this compound, Albendazole, Ivermectin)

The triple-drug combination of ivermectin, this compound, and albendazole (IDA) has emerged as a significantly more effective regimen for accelerating the elimination of lymphatic filariasis in areas not co-endemic for onchocerciasis or loiasis. oup.comwustl.edu Clinical trials have demonstrated the superiority of a single dose of IDA compared to the two-drug combinations (DEC plus albendazole or ivermectin plus albendazole) for clearing larval filarial parasites from the blood of infected persons. oup.com

Studies in heavily infected individuals in PNG showed that IDA was more effective than the DEC and albendazole combination for achieving sustained clearance of Wuchereria bancrofti Mf, with 96% of IDA recipients being Mf negative three years after a single dose. oup.com Follow-up studies indicated that most individuals in this trial remained amicrofilaremic nearly five years after a single dose of IDA. oup.com Similar results, albeit with shorter follow-up periods, were observed in a clinical trial of IDA in individuals with Brugia infection. oup.com

A large multicenter community study involving over 26,000 people in five countries (India, Papua New Guinea, Haiti, Indonesia, and Fiji) provided evidence supporting the use of IDA for LF elimination programs. wustl.edu This study contributed to the World Health Organization's endorsement of IDA for use in LF elimination programs. wustl.edu A systematic review and meta-analysis concluded that triple therapy caused more clearance of microfilaria in the blood compared to dual therapy 12 months after drug administration. nih.gov Another systematic review highlighted that IDA reduces microfilaria formation more than the DEC and albendazole combination. warmadewa.ac.id

Allergic Rhinitis

Exploratory research has suggested this compound as a potential drug for the treatment of allergic rhinitis. nih.govnih.govresearchgate.netjcdronline.org Studies have evaluated its effectiveness in managing the symptoms of allergic rhinitis, particularly in patients with associated eosinophilia. jcdronline.org

A double-blind randomized controlled trial compared the efficacy of this compound with a combination of montelukast and levocetirizine in patients with allergic rhinitis. The study found statistically significant improvement in various parameters, including symptoms, absolute eosinophil count, serum total IgE, and response in skin prick tests, in both treatment groups. nih.govnih.govresearchgate.net Notably, the improvement was reported to be better with this compound compared to the montelukast and levocetirizine combination, and the effects were sustained for three months in the this compound group. nih.govnih.govresearchgate.net

Another study specifically investigated the role of this compound in managing allergic rhinitis with eosinophilia. This descriptive study found that a significant proportion of the study population with allergic rhinitis exhibited eosinophilia. jcdronline.org Treatment with this compound demonstrated utility in reducing symptom scores in these patients and significantly decreased eosinophil scores in both blood and nasal tissue. jcdronline.org These findings suggest its potential as an adjunctive treatment for allergic rhinitis with eosinophilia. jcdronline.org

This compound is thought to exert its effect in allergic rhinitis through various pharmacological actions, including being a potent leukotriene inhibitor and decreasing eosinophil synthesis and numbers, which may reduce the response to allergens. nih.gov

Acute Lung Inflammation Models

Studies utilizing experimental models of acute lung inflammation have provided evidence for the anti-inflammatory effects of this compound. In a mouse model of acute inflammation induced by carrageenan, DEC administration led to reductions in lung injury, polymorphonuclear cell (PMN) migration, nitric oxide (NO) production, and the release of proinflammatory cytokines and COX-2. researchgate.netnih.gov These findings suggest that DEC may be a potential therapeutic agent for acute lung inflammation. nih.gov

Further research in mice demonstrated that DEC attenuates lipopolysaccharide (LPS)-induced acute lung injury by promoting the apoptosis of inflammatory cells. researchgate.net This pro-apoptotic activity was associated with the inactivation of nuclear factor kappa-B (NF-κB). researchgate.net DEC treatment reversed histological and ultrastructural changes, reduced intense cell infiltration and pulmonary edema, and decreased levels of myeloperoxidase (MPO) and NO in LPS-induced lung injury. researchgate.net The study indicated that DEC increased the expression of pro-apoptotic proteins in both intrinsic (Bax, cytochrome c, and caspase-9) and extrinsic (Fas, FADD, and caspase-8) apoptotic pathways, while reducing the expression of the anti-apoptotic protein Bcl-2. researchgate.net These results suggest that DEC may accelerate the resolution of inflammation by stimulating apoptosis of inflammatory cells, highlighting its potential as a pharmacological treatment for acute lung injury. researchgate.net

In a murine model of asthma sensitized with ovalbumin, DEC demonstrated an anti-allergic effect by decreasing cellular infiltration, cytokine levels (IL-4 and IL-5), IgE, eosinophil peroxidase (EPO), and eotaxin2. semanticscholar.org This suggests a role for DEC in blocking pulmonary eosinophilic inflammation. nih.govsemanticscholar.org

Data from studies on acute lung inflammation models:

Potential Role in Other Inflammatory Conditions

Beyond lung inflammation, the anti-inflammatory properties of this compound have been investigated in other experimental models. Research indicates that DEC interferes with the arachidonic acid metabolism, affecting lipoxygenase (LOX) and cyclooxygenase (COX) enzymes. researchgate.net This interference can lead to a reduction in the production of various inflammatory mediators, including thromboxane, prostacyclin, prostaglandins, and leukotrienes. researchgate.net

Studies have shown that DEC can inhibit nuclear transcription factor kappa B (NF-κB) activation, a key regulator of proinflammatory genes such such as TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), and COX-2. researchgate.net This inhibitory effect on NF-κB has been observed in different experimental models of inflammation. researchgate.net

In models of hepatic inflammation and fibrosis induced by carbon tetrachloride (CCl4), DEC treatment has been shown to reduce chronic inflammation and fibrosis by decreasing the expression of inflammatory markers such as IL-1β, COX-2, NF-κB, interferon-γ, and TGF-β. nih.gov DEC treatment in these models led to a reduction in inflammatory infiltrates, liver necrosis, and fibrosis. nih.gov

In an experimental model of alcoholic liver disease, DEC was found to be effective at attenuating proinflammatory cytokines, oxidative stress, and necrosis, suggesting a potential therapeutic use in liver inflammation. researchgate.net Additionally, DEC has shown a role in reducing hepatic cell damage in malnourished mice. researchgate.net

In an isoproterenol-induced acute myocardial infarction (AMI) rat model, DEC treatment significantly suppressed inflammation, iNOS, TGF-β1, COX-2, and PARP protein expression. spandidos-publications.com This suggests a protective effect of DEC in inhibiting NF-κB activation through the PARP pathway in this model. spandidos-publications.com

Potential Role in COVID-19 (Repurposing Studies)

Given its established anti-inflammatory and immunomodulatory activities, this compound has been proposed as a potential repurposed drug for the treatment of COVID-19, particularly focusing on its potential role in addressing COVID-19-related pulmonary fibrosis. scienceopen.comnih.gov

The hypothesis for repurposing DEC for COVID-19 is based on several factors, including its inhibitory effects on arachidonic acid metabolism, which can influence prostaglandin production, and its demonstrated anti-inflammatory actions in animal models of lung inflammation. arxiv.orgresearchgate.net It is postulated that the immunologic effect and enhancement of antibody production by DEC, potentially through the inhibition of LOX and COX enzymes, could contribute to an anti-COVID-19 effect. researchgate.netfrontiersin.org

Furthermore, the anti-fibrotic activity of this compound observed in other inflammatory models makes it a potential candidate for treating the pulmonary fibrosis that can occur as a consequence of COVID-19. scienceopen.comnih.gov While the potential of DEC for COVID-19 treatment has been hypothesized and supported by its known mechanisms and effects in inflammatory models, experimental and clinical studies are needed to assess this possible application. scienceopen.comnih.gov

Data related to the potential role of DEC in COVID-19 (Repurposing Studies):

Role of Genetic Variation in Parasite Populations

Genetic variation within parasite populations can significantly influence drug efficacy and contribute to the development and spread of drug resistance seq.esnih.gov. Genetic diversity can arise from the mixing of genetically different populations, and drug pressure from anthelmintic treatments can also play a significant role in increasing this diversity by selecting for resistant alleles seq.es. Studies using techniques like random amplified polymorphic DNA (RAPD) have shown the existence of genetic variability in W. bancrofti populations seq.es. Higher genetic variability has been detected in densely populated, urban areas, consistent with the expectation that higher transmission rates and larger parasite population sizes may increase genetic diversity nih.gov. The introduction of new drugs or widespread use of existing ones can lead to the selection of alleles encoding resistance, impacting the drug's efficacy against the parasite seq.es.

Single Nucleotide Polymorphisms (SNPs)

Single nucleotide polymorphisms (SNPs) are variations in a single nucleotide base within a DNA sequence nih.gov. While research on specific SNPs directly conferring this compound resistance in filarial nematodes is limited, studies on resistance to other anthelmintics highlight the potential role of SNPs in drug resistance mechanisms nih.govresearchgate.net. For example, specific mutations, which are essentially SNPs, in the β-tubulin gene have been associated with benzimidazole resistance in nematodes seq.es. Research on SNPs in other contexts, such as in drug-resistant genes in Plasmodium falciparum, indicates that recombination and selection can play important roles in shaping the evolution of drug resistance plos.org. Further research is needed to identify specific SNPs in filarial nematodes that may be associated with reduced susceptibility or resistance to this compound.

Combination Therapies to Overcome Resistance

Combination therapy is a key strategy to mitigate the development of drug resistance and improve treatment efficacy nih.govwikipedia.orgfishersci.sefabad.org.trresearchgate.netasm.org. By using multiple drugs with different mechanisms of action, the likelihood of parasites being resistant to all components of the combination simultaneously is reduced. The Global Programme to Eliminate Lymphatic Filariasis (GPELF) currently recommends annual treatment of entire communities with combinations of drugs, such as this compound and albendazole, or ivermectin and albendazole, depending on the co-endemicity of onchocerciasis seq.esmdpi.comwustl.edu.

Recent studies have explored the efficacy of triple-drug therapy involving ivermectin, this compound, and albendazole (IDA) oup.comwustl.edumedrxiv.org. A single dose of this combination has shown superior efficacy in clearing W. bancrofti microfilariae compared to two-drug regimens oup.comwustl.edu. Mathematical models suggest that drug regimens with better activity against microfilariae, like the triple therapy, could significantly improve the chances for eliminating LF oup.com. Furthermore, research indicates potential synergistic effects between this compound and other anthelmintics like emodepside, which targets SLO-1 K+ channels in nematodes asm.orgasm.org. Combinations of DEC and emodepside have shown synergistic effects on muscle membrane potentials and long-term muscle paralysis in Brugia malayi, suggesting their potential in combination therapies to enhance efficacy and potentially overcome resistance asm.orgasm.org.

Data Table: Microfilariae Prevalence Reduction with DEC-Medicated Salt

Data derived from a study on DEC-medicated salt nih.gov.

Data Table: Microfilariae Clearance with Different Regimens

Synergistic Drug Combinations (e.g., this compound and Emodepside)

Research into synergistic drug combinations aims to enhance the efficacy of this compound and potentially overcome reduced susceptibility. Studies have explored the combined effects of this compound and emodepside, an anthelmintic with a distinct mode of action involving the activation of nematode SLO-1 K+ channels. plos.orgnih.gov

Mechanism of Synergy: Investigations in Ascaris suum and Brugia malayi have shed light on the potential mechanisms underlying the synergistic effects of this compound and emodepside.

this compound has been shown to have direct effects on nematode parasites, increasing the activation of SLO-1 K+ currents and potentiating the effects of emodepside in Ascaris suum. plos.orgnih.gov This synergy on membrane potential and SLO-1 K+ current could involve this compound's effects on parasite arachidonic acid and nitric oxide pathways, in addition to emodepside's direct action on SLO-1 channels. plos.org

In Brugia malayi muscles, this compound elicits Ca2+ signals through TRP-2 channels. nih.govasm.org These Ca2+ signals are potentiated by emodepside, which activates SLO-1 Ca2+-activated K+ channels, the putative target of emodepside. nih.govnih.govasm.org The combination of this compound and emodepside leads to a larger Ca2+ signal compared to either compound alone. nih.govasm.org

Observed Effects: The synergistic relationship between emodepside and this compound has been observed to result in the potentiation of flaccid paralysis in Brugia, which is dependent on TRP-2 channels. nih.govresearchgate.net This combination also increases membrane potential hyperpolarization in the muscles of Ascaris suum. researchgate.net

These findings suggest the potential for combining this compound and emodepside as an anthelmintic treatment, predicted to be synergistic. plos.orgnih.gov While emodepside shows effects against filarial nematodes and is being investigated for river blindness, its in vivo potency against some filarial parasites like Brugia is limited, highlighting the potential benefit of combination therapy. nih.gov

Immunological Mechanisms Underlying the Mazzotti Reaction

The Mazzotti reaction is fundamentally an immunological response to the antigens released from dying microfilariae. capes.gov.brresearchgate.netaltmeyers.org When microfilariae are damaged or killed by DEC, parasitic antigens are released into the host organism, triggering an inflammatory immune reaction. researchgate.netaltmeyers.org

The rapid killing of microfilariae by DEC leads to the release of a large amount of parasitic antigens. researchgate.netaltmeyers.org These antigens provoke an exuberant inflammatory response in the host. altmeyers.org This inflammatory reaction can be localized or generalized. researchgate.netug.edu.gh The clinical features of the reaction are thought to be due to the effects of mediators secreted from inflammatory cells at the sites where microfilariae are being destroyed. researchgate.netug.edu.gh

Eosinophils play a prominent role in the immunological response associated with the Mazzotti reaction. taylorandfrancis.comcapes.gov.brnih.gov Eosinophil degranulation, with the subsequent release of inflammatory mediators into the tissues and peripheral blood, is a significant feature observed in patients experiencing post-treatment reactions. capes.gov.brnih.govasm.org This degranulation occurs with a time course generally consistent with what would be required of an initiator of such reactions. capes.gov.brnih.gov Evidence suggests eosinophil attachment to and eosinophil-mediated degradation of dying filarial parasites in biopsy material from humans undergoing the Mazzotti reaction. taylorandfrancis.com Studies have shown increased levels of eosinophil-associated proteins like Eosinophil Derived Neurotoxin (EDN) and Major Basic Protein (MBP) which peak within the first few days of treatment, coinciding with the infiltration and degranulation of eosinophils in the affected tissues, such as the skin. asm.orgfrontiersin.org

While eosinophil degranulation is prominent, the reaction does not appear to primarily require the generation of circulating immune complexes or systemic complement activation, even in generalized reactions. researchgate.netug.edu.gh Other inflammatory mediators and pathways, such as kinins, prostaglandins, leukotrienes, and platelet-derived factors, may also be involved, but current evidence does not strongly implicate them as primary initiators of the response. capes.gov.brnih.gov

Cytokines play a crucial role in regulating the immune response during parasitic infections. parasite-journal.org In the context of the Mazzotti reaction, specific cytokines are implicated in the inflammatory cascade. Serum levels of Interleukin-5 (IL-5), a cytokine known to induce eosinophilia, have been observed to rise sharply after DEC treatment, preceding the increase in eosinophil levels. taylorandfrancis.com This suggests a temporal relationship between IL-5 and the subsequent development of eosinophilia seen in these patients. taylorandfrancis.com The mechanism by which IL-5 is selectively induced to high levels is not fully clear but may involve the presentation of antigens from dead and dying parasites to T cells, skewing the cytokine response towards a high IL-5 production. taylorandfrancis.com IL-5 has been detected in the Mazzotti reaction that can follow treatment of onchocerciasis. nih.gov Other cytokines examined, such as IL-3 and GM-CSF, were not consistently detectable in the serum before or after treatment in some studies. taylorandfrancis.com Pro-inflammatory cytokines like TNF-α and IL-6 are also involved in inflammatory processes and immune responses in parasitic diseases, although their specific initiating role in the Mazzotti reaction requires further clarification. nih.govexplorationpub.com

Eosinophil Degranulation and Inflammatory Mediators

Clinical Manifestations and Severity

The clinical manifestations of the Mazzotti reaction can vary in severity and typically appear within hours to days after DEC administration. researchgate.netaltmeyers.org Common symptoms include a severe pruritic skin rash, fever, headache, muscle and joint pain (arthralgia), lymphadenopathy (swollen lymph nodes), tachycardia (rapid heart rate), hypotension (low blood pressure), edema (swelling), and abdominal pain. taylorandfrancis.comcapes.gov.brwikipedia.orgontosight.aialtmeyers.orgnih.gov Ocular involvement can also occur, with inflammatory reactions in the anterior and posterior segments of the eye. who.intajtmh.org In severe cases, complications such as bronchospasm, thrombocytopenia, and even anaphylaxis have been reported. ontosight.ai While nearly all patients treated for onchocerciasis with microfilaricides may experience some form of Mazzotti reaction, most events are transient and self-limiting. tandfonline.com Only a small percentage of individuals report moderate to severe reactions. taylorandfrancis.com

Risk Factors (e.g., Microfilarial Load, Co-infection with Onchocerciasis)

The occurrence and intensity of the Mazzotti reaction are strongly correlated with the intensity of the filarial infection, specifically the microfilarial load. capes.gov.brwikipedia.orgaltmeyers.orgnih.gov Patients with higher microfilarial loads are more likely to experience more severe reactions. taylorandfrancis.comtandfonline.com Studies have definitively shown a correlation between the severity of the Mazzotti reaction, including symptoms like hypotension, fever, adenitis, and pruritus, and the intensity of infection as determined by skin snip quantification. nih.govajtmh.org Peripheral blood eosinopenia and neutrophilia also correlate with infection intensity. nih.govajtmh.org

Co-infection with other filarial parasites, such as Loa loa, can also increase the risk of severe adverse reactions, including potentially life-threatening encephalopathy, particularly when using medications like ivermectin in areas where loiasis is endemic. tandfonline.comnih.gov While DEC is not the preferred treatment for onchocerciasis in co-endemic areas due to the risk of severe Mazzotti reactions and exacerbation of ocular pathology, the principle of higher parasite load correlating with increased reaction severity is relevant across microfilaricidal treatments. gre.ac.uk

Double-Blind Studies

Double-blind studies are frequently employed in DEC research to prevent bias from both participants and researchers knowing the assigned treatment. In this design, neither the patient nor the investigator is aware of whether the patient is receiving DEC or the control. A double-blind, placebo-controlled study in Tanzania evaluated DEC for the treatment of hydrocoele. nih.gov Another double-blind trial in Tahiti compared the efficacy and tolerability of single doses of ivermectin and DEC for treating Wuchereria bancrofti carriers. nih.gov A randomized double-blind clinical trial in Thailand investigated a single dose of doxycycline in combination with DEC for bancroftian filariasis. thaiscience.info

Bioequivalence Studies

Bioequivalence studies are conducted to determine if different formulations or generic versions of DEC deliver the same amount of the active compound to the bloodstream over the same period as a reference product. These studies are crucial for ensuring that different products are interchangeable. Guidance for the design of bioequivalence studies for DEC recommends a single-dose cross-over design, typically conducted in the fed state as DEC is preferably administered with food. who.intwho.int A minimum sample size of 14 subjects is recommended, with intensive blood sampling in the initial hours to characterize the maximum concentration (Cmax) of DEC. who.intwho.int A washout period of 7 days is considered sufficient based on DEC's elimination half-life. who.intwho.int LC-MS/MS analytical methodology is indicated as suitable for measuring DEC in human plasma for these studies. who.intwho.int

High-Performance Liquid Chromatography (HPLC)

High-Performance Liquid Chromatography (HPLC) is a widely used technique for the analysis of this compound in various samples, including pharmaceutical formulations and medicated salt. Several RP-HPLC methods have been developed and validated for the estimation of DEC.

One method for determining DEC in medicated salt utilizes a Phenomenex C8 column with a mobile phase composed of acetonitrile and phosphate buffer (20 mM KH₂PO₄, adjusted to pH 3.2 with 10% ortho-phosphoric acid) in a 1:9 ratio, at a flow rate of 1.5 ml/min. UV detection is performed at 210 nm. This method demonstrated a coefficient of variation below 10% in the range of 1-25 µg/ml and a minimum detectable level of 0.5 µg/ml. nih.govresearchgate.net Analysis of medicated salt samples using this method showed varying DEC content depending on the preparation method. nih.govresearchgate.net

Another RP-HPLC method for the simultaneous estimation of this compound citrate and cetirizine hydrochloride in formulations employs a Phenomenex C18 column with a mobile phase of acetonitrile and mixed phosphate buffer (KH₂PO₄ and K₂HPO₄, adjusted to pH 3.0 with 10% orthophosphoric acid) in a 60:40 ratio, at a flow rate of 1 ml/min. UV detection is carried out at 220 nm, which is an isosbestic point for both compounds. The method showed linearity in the range of 24-144 µg/ml for this compound citrate with a correlation coefficient of 0.998.

A stability-indicating RP-HPLC method for the simultaneous estimation of this compound citrate, guaiphenesin, and chlorpheniramine maleate in tablet dosage forms uses a luna phenyl-hexyl column with an isocratic mobile phase of 0.1% triethylamine buffer (pH adjusted to 2.5 with orthophosphoric acid) and acetonitrile (50:50 v/v) at a flow rate of 1.0 ml/min and UV detection at 210 nm. The retention time for this compound citrate was found to be 7.76 min. innovareacademics.in The method was linear in the range of 1-15 µg/ml for this compound citrate with a correlation coefficient of 0.999. innovareacademics.in

HPLC methods are also suitable for pharmacokinetics studies and can be scaled for preparative separation to isolate impurities. sielc.com For LC-MS compatible applications, the mobile phase typically uses formic acid instead of phosphoric acid. sielc.com

Mass Spectrometry (LC-MS/MS)

Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is a sensitive and selective technique used for the quantification of this compound, particularly in biological matrices like human plasma, for clinical pharmacokinetic studies. researchgate.netresearchgate.netnih.govnih.govwpmucdn.com

A rapid and sensitive LC-MS/MS method has been developed and validated for the simultaneous quantitation of this compound, albendazole, and albendazole metabolites in human plasma. researchgate.netnih.govnih.gov This method utilizes solid phase extraction for sample preparation and employs a reversed-phase column (Acquity UPLC® BEH C18) with gradient elution using mobile phases containing formic acid. researchgate.netnih.govnih.gov Analytes are monitored using MS/MS with an electrospray ionization source in positive multiple reaction monitoring mode. researchgate.netnih.govnih.gov The method demonstrated linearity for DEC over a concentration range of 1-2000 ng/mL with a correlation coefficient (r²) of 0.998 or better. researchgate.netnih.gov The lower limit of quantitation (LLOQ) for DEC was reported as 1 ng/mL in one study. researchgate.netnih.gov Another LC-MS method reported an LLOQ of 4 ng/mL for DEC in human plasma with a linear range of 4–2200 ng/mL. researchgate.netwpmucdn.com This LC-MS assay requires a smaller plasma sample volume (0.25 mL) compared to some previous methods. wpmucdn.com

LC-MS/MS methods offer high sensitivity and specificity, making them valuable for accurately determining drug concentrations in complex biological samples and for drug-drug interaction studies. researchgate.netnih.gov

Spectrophotometric Methods (e.g., UV, Folin-Ciocalteu Reagent)

Spectrophotometric methods, including UV spectroscopy and methods utilizing reagents like Folin-Ciocalteu, have been developed for the determination of this compound in bulk drug and pharmaceutical formulations. scielo.brfabad.org.trscielo.brresearchgate.net

UV spectrophotometry can be used to determine DEC by measuring absorbance in acidic solutions. For example, methods measuring absorbance at 210 nm in 0.1M HCl or at 209 nm in 0.1M H₂SO₄ have been described. researchgate.net However, these UV methods may have higher lower limits of quantitation (LLOQ) compared to chromatographic techniques. researchgate.net

Methods employing the Folin-Ciocalteu (F-C) reagent are based on the formation of a blue chromogen due to the reduction of tungstate and/or molybdate in the reagent by DEC in an alkaline medium. researchgate.netfabad.org.tr This colored species has an absorption maximum at 760 nm. researchgate.netfabad.org.tr The absorbance is linearly dependent on the concentration of DEC, obeying Beer's law over a specific concentration range (e.g., 10-100 μg mL⁻¹). researchgate.netfabad.org.tr This method has been successfully applied to the determination of DEC in bulk powder, tablets, and syrup. fabad.org.tr

Other spectrophotometric methods involve reactions with reagents like iodate and iodide mixture, where the liberated iodine is measured spectrophotometrically at 370 nm or as the iodine-starch complex at 570 nm. scielo.brscielo.br These methods show linear calibration curves over specific concentration ranges. scielo.brscielo.br Extractive spectrophotometric methods based on the formation of ion-pair complexes between DEC and acidic dyes like Tropaeolin 000 have also been developed, with absorbance measured at 490 nm. researchgate.netresearchgate.net

Spectrophotometric methods are often considered simple and rapid for the quantification of DEC. researchgate.netfabad.org.tr

Gas Chromatography (GC)

Gas Chromatography (GC) has been used for the analysis of this compound, particularly for its determination in human plasma for pharmacokinetic studies. researchgate.netscielo.brnih.gov

A sensitive and selective GC method using flame ionization detection has been developed for DEC in human plasma. nih.gov This method involves solid phase extraction of DEC and an internal standard (1-diethylcarbamyl-4-ethyl piperazine HCl) from plasma. nih.gov Separation is achieved on a capillary column (e.g., Heliflex® AT-35). nih.gov The assay was linear in the concentration range of 100-2000 ng/ml for DEC in human plasma, demonstrating good precision and accuracy. nih.gov The retention times for DEC and the internal standard were approximately 5.5 and 7.28 minutes, respectively. nih.gov

While GC methods have been utilized, the analysis of DEC in plasma by GC can be complicated by the presence of its metabolite, DEC-N-oxide, which can be converted to a substance that coelutes with DEC under certain GC conditions. researchgate.net

Proton Magnetic Resonance (PMR) Spectroscopy

Proton Magnetic Resonance (PMR) spectroscopy, also known as ¹H NMR, has been employed for the quantitative determination of this compound in standard mixtures and tablet formulations. scielo.brtandfonline.comtandfonline.com

A PMR procedure using deuterium oxide as a solvent and maleic acid as an internal standard has been developed. tandfonline.com The method is based on integrating the characteristic peaks of DEC and the internal standard in the PMR spectrum. tandfonline.com This procedure has been reported as simple, specific, and accurate for the quantitative analysis of this compound citrate. tandfonline.comtandfonline.com The average recovery of pure DEC in standard mixtures using this method was reported as 100.03 ± 0.11% w/w. tandfonline.comtandfonline.com

Low-Tech Analytical Methods for Field Use (e.g., Back-Titration)

In settings where access to advanced analytical instrumentation is limited, low-tech methods are valuable for the analysis of this compound, particularly in formulations like medicated salt used in mass drug administration programs. nih.govplos.orgresearchgate.net

A simple titration-based assay, specifically a back-titration procedure, has been developed for determining this compound citrate concentrations in medicated salt. nih.govplos.orgresearchgate.net This method capitalizes on the acidic nature of this compound citrate. nih.govplos.orgresearchgate.net A known excess of a strong base (e.g., sodium hydroxide) is added to a sample containing DEC citrate, reacting completely with the acidic protons. nih.govplos.org The remaining excess base is then back-titrated with a standard acid (e.g., HCl) using a common indicator like phenolphthalein to determine the neutralization point. nih.govplos.org

Direct titration of DEC citrate with a base is not analytically useful due to the range of pKa values in the citrate component, which results in an unclear endpoint. nih.govplos.org The back-titration method provides a clear endpoint and can be carried out with basic laboratory equipment such as a balance, volumetric glassware, and burets, without the need for electrical power. nih.govplos.orgresearchgate.net This makes it suitable for quality control and field analysis in resource-limited settings. nih.govplos.org Comparison studies have been conducted to evaluate this titration method against HPLC. researchgate.net

Mass Drug Administration (MDA) Strategies

Mass Drug Administration is a key strategy in LF elimination programs, aiming to reduce parasite density in infected individuals and lower infection prevalence in communities to levels where transmission is no longer sustainable. dovepress.com DEC is a primary drug used in MDA, often in combination with other antifilarial drugs. dovepress.comasm.org

The GPELF initially recommended single-dose, two-drug regimens administered annually. dovepress.com Outside of areas co-endemic for onchocerciasis or loiasis, the recommended combination typically includes this compound citrate and albendazole (DA). dovepress.commdpi.comnih.govplos.org In areas co-endemic for onchocerciasis, ivermectin and albendazole (IA) are used. mdpi.comnih.gov For areas co-endemic with loiasis, albendazole is administered twice yearly. nih.gov

More recently, a triple-drug therapy combining ivermectin, this compound, and albendazole (IDA) has shown superior efficacy in clearing microfilariae compared to the DA regimen in clinical trials. plos.orgplos.orgajtmh.orgoup.comnih.govmedrxiv.org The WHO endorsed the use of IDA in specific settings outside of onchocerciasis-endemic areas to accelerate LF elimination. nih.govmedrxiv.orgplos.orgplos.org Studies have demonstrated that IDA can achieve sustained microfilariae clearance for up to three years after a single dose. asm.orgplos.org

Research findings highlight the impact of repeated rounds of MDA with DEC and albendazole. For instance, a study in Papua New Guinea showed that three rounds of MDA decreased microfilaremia rates significantly. plos.org

Table 1: Impact of MDA with DEC + Albendazole on Microfilaremia and Antigenemia Rates in Papua New Guinea plos.org

Another study in Egypt demonstrated that annual MDA with DEC and albendazole significantly reduced prevalence rates of microfilaremia and circulating filarial antigenemia, as well as mosquito infection rates, suggesting that elimination was likely after five rounds of MDA. nih.gov

Table 2: Reduction in Infection and Transmission Indicators After MDA in Egypt nih.gov

This compound-Medicated Salt Programs

In addition to tablet-based MDA, the administration of DEC through medicated salt has been explored and implemented as a community-based control measure for lymphatic filariasis. nih.govajtmh.orgnih.gov This strategy involves adding low concentrations of DEC to common salt consumed by the population over several months to a year. nih.govplos.org

DEC-medicated salt played a significant role in China's filariasis control program and has shown success in trials conducted in countries like India, Brazil, and Tanzania. ajtmh.orgnih.govajtmh.org Studies have indicated that DEC-fortified salt is effective in significantly reducing microfilaremia prevalence and density. nih.gov For instance, in China, fortified salt with varying DEC concentrations administered over 4-6 months resulted in substantial reductions in Mf prevalence and density one year post-intervention. nih.gov A study in the Andaman Islands, India, showed that the combination of annual MDA-DA and DEC-fortified salt led to a greater reduction in Mf prevalence compared to MDA alone. nih.gov

The use of DEC-medicated salt is considered a simple, rapid, safe, inexpensive, efficient, prophylactic, and practical approach for filariasis elimination. nih.gov

Sustaining Microfilarial Clearance

While DEC is effective at clearing microfilariae, sustaining this clearance over the long term can be challenging, particularly with single-dose regimens of DEC and albendazole. asm.org The reappearance of microfilariae after treatment necessitates repeated annual rounds of MDA, typically for at least 5 years, which is the approximate lifespan of adult worms. asm.org

The introduction of the triple-drug therapy (IDA) offers a potential solution to this challenge, as it has demonstrated the ability to sustain microfilarial clearance for longer periods after a single administration compared to the DA regimen. asm.orgplos.org However, persistent microfilaremia after MDA can still occur, often attributed to individuals not taking the medications as prescribed rather than drug failure. ajtmh.org

Ensuring High Coverage and Compliance

Achieving and maintaining high coverage and compliance rates in MDA programs are critical for interrupting transmission and achieving elimination. The recommended minimum epidemiological coverage for effective reduction of LF transmission is at least 65% of the total eligible population in an implementation unit. plos.orgwho.intnih.gov However, consistently reaching and sustaining this level can be difficult. journalofcomprehensivehealth.co.infrontiersin.orgplos.org

Factors influencing non-coverage and non-compliance include unawareness of MDA, absence from home, travel, refusal to take the drug, illness, and fear of side effects. journalofcomprehensivehealth.co.infrontiersin.orgplos.orginfontd.org Studies have shown variability in compliance rates, with some populations reporting high distribution but lower consumption of the drugs. journalofcomprehensivehealth.co.ininfontd.org

Efforts to improve coverage and compliance involve engaging communities in planning and implementation, addressing local concerns, ensuring drug distributors are trusted and well-trained, and providing clear information about the program. nih.govjournalofcomprehensivehealth.co.in Strategies to enhance administration and ensure directly observed treatment can also improve ingestion rates. ajtmh.orgnih.gov

Challenges also exist in monitoring and evaluating coverage accurately, as reported data may not always reflect actual drug ingestion. dovepress.comnih.gov Innovative approaches and improved surveillance systems are needed to identify and reach individuals who are missed during MDA rounds, as these individuals can serve as reservoirs of infection and pose a threat to elimination efforts. medrxiv.orgfrontiersin.org

Addressing Emerging Drug Resistance

This compound (DEC) has been a cornerstone in the treatment and control of lymphatic filariasis for many decades. Despite its widespread use since 1947, confirmed resistance to DEC in the primary target parasites, such as Wuchereria bancrofti and Brugia malayi, has not been widely reported nih.gov. However, the potential for drug resistance to emerge remains a significant concern, particularly with large-scale mass drug administration (MDA) programs implemented globally to eliminate lymphatic filariasis seq.esmdpi.com.

While widespread resistance to DEC has not been confirmed, it is recognized that susceptibility to the drug is not 100% in all cases of lymphatic filariasis treatment seq.esmdpi.comnih.gov. Some studies and clinical observations have indicated that a small percentage of treated patients may not respond to DEC despite multiple courses of therapy oup.com. The reasons for these treatment failures are not fully understood and could involve factors such as inadequate drug concentrations, inherent variability in parasite susceptibility, or the host's immune response oup.com.

Research into the mechanisms of action of DEC is ongoing, and a better understanding of how the drug affects parasites is crucial for anticipating and addressing potential resistance sciencedaily.com. While it was historically thought that DEC primarily acted by sensitizing microfilariae to the host's immune system, more recent research suggests direct effects on the parasites sciencedaily.comdrugbank.complos.org. Studies using Ascaris suum, a related nematode, have shown that DEC can directly affect voltage-activated potassium channels (SLO-1) in the parasite, suggesting a direct anthelmintic effect plos.orgnih.gov. This understanding of direct mechanisms could help in identifying potential pathways for resistance development.

The difficulty in demonstrating anthelmintic resistance in filarial parasites like W. bancrofti is partly due to the challenges in culturing these parasites in animal models and the lack of a free-living stage seq.es. Parasitological evidence of resistance often relies on demonstrating the persistence of parasites after treatment over an extended period seq.es.

Monitoring for emerging resistance is a critical component of elimination programs. While specific data tables detailing confirmed DEC resistance are scarce in the available literature, the ongoing surveillance within MDA programs for lymphatic filariasis implicitly serves to detect potential shifts in parasite susceptibility that could indicate emerging resistance. The Global Programme to Eliminate Lymphatic Filariasis (GPELF) utilizes strategies such as repeated annual doses of antifilarial drugs and transmission assessment surveys to monitor the impact of interventions plos.orgoup.com. Although these monitoring efforts are primarily aimed at assessing the reduction of infection prevalence and interruption of transmission, they would likely identify areas where drug efficacy might be declining.

The development of new diagnostic tools, such as antigen tests for adult worms, which can be performed at any time, offers potential for improved monitoring of infection prevalence and could potentially aid in detecting subtle changes in parasite populations that might correlate with reduced drug efficacy nih.gov.

The potential for resistance also underscores the importance of combination therapies. The co-administration of DEC with other antifilarial drugs, such as albendazole and ivermectin (IDA regimen), has shown increased effectiveness in clearing microfilariae compared to two-drug regimens, which could potentially mitigate the risk of resistance development by targeting parasites through multiple mechanisms plos.orgoup.com.

Further research is needed to fully understand the mechanisms of DEC action and to develop sensitive methods for detecting and monitoring potential drug resistance in filarial parasites nih.gov. Studies exploring the genetic diversity of filarial parasites and potential resistance-associated alleles are also important for proactive resistance management seq.es.