Miltefosine

Mitochondrial Dysfunction Induction

Cytochrome C Oxidase Inhibition

A key mechanism of action for miltefosine involves its impact on mitochondrial function, specifically the inhibition of cytochrome c oxidase (Complex IV) within the parasite's electron transport chain. This inhibition leads to a notable decrease in the oxygen consumption rate and a subsequent reduction in intracellular ATP levels in parasites such as Leishmania donovani. mdpi.comdrugbank.commdpi.comasm.org This disruption of oxidative phosphorylation is a critical factor contributing to parasitic death. mdpi.com

Research findings indicate a dose-dependent effect of this compound on the mitochondrial electrochemical potential (Δφm) in L. donovani, with maximal effects observed at concentrations around 40 µM. mdpi.com Studies on this compound-resistant Leishmania infantum parasites have shown an increased concentration of several subunits of the cytochrome c oxidase complex (Complex IV) and ATP synthase subunits (Complex V), suggesting that resistant parasites may develop a highly active oxidative phosphorylation pathway to counteract this compound's effects. mdpi.com

Table 1: Impact of this compound on Mitochondrial Components in Leishmania infantum

Reactive Oxygen Species Generation

This compound induces the production of reactive oxygen species (ROS) within the mitochondria of parasites. patsnap.comfrontiersin.orgnih.gov This increase in ROS levels leads to oxidative damage to essential cellular components, including lipids, proteins, and DNA, which ultimately contributes to the death of the parasite. patsnap.comfrontiersin.org

Studies have shown that this compound-tolerant Leishmania donovani parasites exhibit a greater ability to resist ROS compared to sensitive parasites, and in resistant strains, the this compound-induced increase in ROS is not observed, suggesting a more efficient ROS scavenging or compensatory mechanism. itg.beresearchgate.net This generation of oxidative stress is also observed in other pathogens, such as Candida albicans, where this compound increases intracellular ROS production and induces apoptosis. nih.govresearchgate.net

Apoptosis Induction Pathways

This compound is known to induce an apoptosis-like cell death process in Leishmania parasites and other cell types. drugbank.compatsnap.commdpi.comfrontiersin.org This programmed cell death is characterized by several features observed in metazoan apoptosis, including cell shrinkage, nuclear DNA condensation, DNA fragmentation into oligonucleosome-sized fragments, and externalization of phosphatidylserine to the outer leaflet of the plasma membrane. frontiersin.orgnih.gov

In Leishmania donovani, this compound-induced apoptosis is not merely a direct toxic effect, as these changes are not detected in this compound-resistant clones. nih.gov Research indicates that this compound activates specific apoptotic pathways. For instance, in Leishmania major, this compound appears to activate Leishmania metacaspase (LmjMCA), a cysteine protease involved in programmed cell death. d-nb.info In mammalian cells (e.g., U937 cells), this compound (hexadecylphosphocholine) induces the activation of caspase-9, -3, and -8 via the intrinsic pathway, leading to cytochrome c release and activation/relocation of Bax to the mitochondria. nih.gov A lysosomal pathway, characterized by partial lysosomal rupture and cathepsin B activation, is also implicated in this compound-induced apoptosis in these cells. nih.gov

Effects on Host Immune Cell Function

This compound influences various host immune cell functions, promoting a pro-inflammatory response crucial for combating parasitic infections. mdpi.comnih.govresearchgate.netoup.com

Monocytes and Macrophages: this compound upregulates the expression of activation markers like CD16 and costimulatory molecules such as CD86 on circulating monocytes, while reducing CD14 expression. nih.govresearchgate.netoup.com This shift indicates an enhancement of the monocyte population towards a pro-inflammatory phenotype. nih.govresearchgate.netoup.com this compound also enhances M1 macrophage polarization, leading to increased production of pro-inflammatory cytokines, nitric oxide (NO), and ROS, which creates a hostile environment for parasite survival. mdpi.com

T-helper (Th) Cells: this compound induces Th1-type immune responses, which are essential for controlling Leishmania infections. mdpi.comresearchgate.netnih.gov Studies have shown this compound-induced activation of Th1 cytokines, particularly increased Interferon-gamma (IFN-γ) and Interleukin-12 (IL-12), which are critical for overcoming the Leishmania-driven Th2 response that often characterizes severe disease. researchgate.netnih.govnih.gov This is supported by observations of increased IFN-γ levels in macrophages of Leishmania-infected animals and an 8-fold rise in IL-12 levels in peripheral blood mononuclear cells (PBMCs) from visceral leishmaniasis patients after this compound treatment. nih.gov

Eosinophils and Mast Cells: this compound has been shown to suppress the activation of human eosinophils, leading to a decreased inflammatory response that can ameliorate tissue destruction. mdpi.com It also inhibits mast cell degranulation, microtubule reorganization, and chemotaxis, affecting lipid raft modulation and calcium-dependent protein kinase C (PKC) activities. mdpi.com

Influence on Pro-inflammatory Cytokine Production

This compound significantly influences the production of pro-inflammatory cytokines, playing a vital role in shaping the host's immune response against parasitic infections. patsnap.comnih.govnih.govresearchgate.netoup.com

Research in patients with post kala-azar dermal leishmaniasis (PKDL) demonstrated that this compound treatment led to a significant increase in circulating levels of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), Interleukin-1 beta (IL-1β), and Interleukin-8 (IL-8). nih.govresearchgate.netoup.com Concurrently, there was a decrease in anti-inflammatory cytokines, such as Interleukin-10 (IL-10), Transforming Growth Factor-beta (TGF-β), Interleukin-4 (IL-4), and Interleukin-13 (IL-13). nih.govresearchgate.netoup.com This cytokine modulation by this compound collectively indicates the triggering of a robust Th1 response that facilitates parasite elimination. nih.govresearchgate.netoup.com

Table 2: Influence of this compound on Pro-inflammatory Cytokines in PKDL Patients

This enhancement of pro-inflammatory cytokine secretion, coupled with increased serum nitrite levels and decreased serum arginase activity, underscores this compound's macrophage-activating potential. nih.govresearchgate.net

Absorption and Distribution Studies

This compound is administered orally and exhibits a slow absorption process from the gastrointestinal tract. drugbank.com In animal models, the absolute bioavailability is high, reaching 82% in rats and 94% in dogs. drugbank.com The time to reach maximum plasma concentration (Tmax) varies, ranging from 4 to 48 hours. oup.com While the absolute bioavailability in humans has not been determined due to the risk of hemolysis with intravenous administration, a gastrointestinal absorption rate of 0.416 h⁻¹ has been estimated using a two-compartment population pharmacokinetic model. drugbank.com

In vitro studies using Caco-2 cells suggest a dual mechanism for absorption. At concentrations below 50 μM, this compound appears to cross membranes primarily through a non-saturable, passive paracellular diffusion that is independent of pH. oup.com Above this concentration, a saturable, likely active carrier-mediated transport mechanism becomes involved. oup.com

Once absorbed, this compound is widely distributed throughout the body. oup.com Studies in rats using radiolabelled this compound showed extensive uptake in various tissues, with the highest concentrations found in the liver, lungs, kidneys, and spleen. oup.com Another study in rats confirmed high drug concentrations in the adrenal glands, kidneys, spleen, and skin. oup.com this compound is highly bound to plasma proteins, with binding rates between 96% and 98%. drugbank.com It primarily binds to serum albumin (97%) and, to a lesser extent, low-density lipoprotein (3%). drugbank.com

Table 1: Bioavailability and Tmax of this compound in Different Species

Metabolic Pathways and Elimination Research

The metabolism of this compound is a slow process primarily mediated by phospholipases, particularly phospholipase D. drugbank.comoup.com This enzymatic action cleaves the molecule, releasing choline and hexadecanol. drugbank.com These metabolites are endogenous compounds that can be reutilized in the body's physiological processes. oup.com Choline can be used for the synthesis of acetylcholine or in the formation of cell membranes, while hexadecanol can be oxidized to palmitic acid and used in the biosynthesis of other fatty acids. drugbank.comoup.com In vitro studies have shown that this compound is a substrate for reconstituted phospholipase D, and other research suggests that both phospholipase C and D can hydrolyze it. oup.com Notably, no oxidative metabolism of this compound by cytochrome P450 (CYP) enzymes has been observed, suggesting a low potential for metabolic drug-drug interactions at the CYP level. oup.comfda.gov

Elimination of this compound is almost entirely through these metabolic degradation pathways. oup.com Urinary excretion of the unchanged drug is minimal, accounting for less than 0.2% of the administered dose. oup.com Fecal excretion has not been extensively studied in humans but is thought to be negligible due to the drug's very long elimination half-life and high accumulation. oup.com However, a study in Beagle dogs did show slow fecal excretion, accounting for about 10% of the total clearance. oup.com

Long Half-Life Implications in Treatment and Resistance Development

A defining characteristic of this compound's pharmacokinetics is its extremely long elimination half-life. oup.com This slow elimination leads to drug accumulation in the body until the end of a standard 28-day treatment course. oup.com Pharmacokinetic modeling has identified a two-compartment disposition model, with a primary elimination half-life of approximately 7 days and a terminal elimination half-life of about 30.9 days. asm.org In some cases, the half-life has been reported to be between 150 and 200 hours (about 6 to 8 days). oup.comum.es

This prolonged presence in the body at subtherapeutic concentrations for weeks or even months after treatment completion is a significant concern for the development of drug resistance. asm.orgnih.gov The long half-life, coupled with a lengthy treatment course, may facilitate the selection of resistant parasites. oup.comnih.gov In vitro studies have demonstrated that Leishmania promastigotes can rapidly develop resistance when cultured in the presence of this compound. asm.orgnih.gov The primary mechanisms of this acquired resistance involve decreased intracellular accumulation of the drug, either through increased efflux by P-glycoprotein transporters or by reduced uptake due to inactivation of the this compound transporter (LdMT) and its beta subunit (LdRos3). nih.gov

Population Pharmacokinetic Modeling and Variability

Population pharmacokinetic (PK) modeling has been instrumental in understanding the variability in this compound exposure among different patient populations. nih.govoup.com These studies, often using nonlinear mixed-effects modeling software like NONMEM, have helped to characterize the drug's disposition and identify factors contributing to inter-individual differences. nih.govoup.com

A key finding from population PK analyses is that a two-compartment model with first-order absorption best describes this compound's pharmacokinetics. asm.orgnih.gov These models have confirmed the long initial and terminal half-lives of the drug. oup.com

Significant variability in this compound exposure has been observed, particularly between adults and children. asm.org Studies have shown that children often have lower plasma concentrations than adults when treated with the standard weight-based dosing, which may contribute to higher treatment failure rates in this group. asm.orgoup.com Population PK modeling has demonstrated that allometric scaling, particularly using fat-free mass (FFM), can reduce the between-subject variability in parameters like clearance and volume of distribution more effectively than linear weight-based scaling. asm.orgresearchgate.net This has led to proposals for allometric dosing algorithms to achieve more consistent and optimal drug exposure across different age and weight groups, potentially improving clinical outcomes. asm.orgoup.com Furthermore, disease state can influence pharmacokinetics, with studies showing that this compound bioavailability is lower at the start of treatment in visceral leishmaniasis patients compared to those with post-kala-azar dermal leishmaniasis, likely due to disease-related malabsorption. diva-portal.org

Table 2: this compound Pharmacokinetic Parameters from Population Modeling

Concentration-Effect Relationships in Target Pathogens

The effectiveness of this compound is linked to achieving and maintaining adequate concentrations at the site of infection. plos.org In vitro studies have established the 90% effective concentration (EC90) for Leishmania donovani to be in the range of 5.8–9.1 μg/mL. plos.org Clinical studies have shown that plasma concentrations in treated patients often exceed these in vitro EC90 values. plos.org

However, the relationship is complex because Leishmania parasites reside intracellularly. Therefore, intracellular drug concentrations are more relevant to the therapeutic effect than plasma concentrations. plos.org It has been proposed that the time the drug concentration remains above the in vitro intracellular EC90 is a predictor for relapse in visceral leishmaniasis. oup.com

Exposure-response relationships have been explored in clinical settings. In patients with cutaneous leishmaniasis, a significant link between this compound exposure, measured as the area under the plasma concentration-time curve (AUC), and the probability of cure has been established. oup.com A target AUC from day 0 to 28 of >535 mg·day/L was associated with a greater than 95% probability of cure. oup.com Simulations based on this target have highlighted that a larger percentage of children compared to adults fail to reach this exposure level with standard linear dosing, reinforcing the need for optimized dosing strategies in pediatric populations. oup.com this compound's mechanism of action involves disrupting lipid-dependent cell signaling pathways and inducing apoptosis-like cell death in the parasite. drugbank.com It has been shown to inhibit cytochrome-c oxidase in the mitochondria, leading to mitochondrial dysfunction. drugbank.com

Cellular and Molecular Responses Post-Exposure

This compound's efficacy as a broad-spectrum antimicrobial and anticancer agent stems from its multifaceted interaction with cellular and molecular processes. drugbank.com Its primary mechanisms involve the induction of apoptosis and the disruption of lipid-dependent signaling pathways. drugbank.comoup.com These actions are observed in both parasitic protozoa, such as Leishmania, and in neoplastic cells. drugbank.comoup.com

Apoptosis Induction

This compound is a potent inducer of apoptosis, or programmed cell death, in susceptible organisms and cells. oup.comepa.gov This process is characterized by a series of distinct morphological and biochemical events, including cell shrinkage, externalization of phosphatidylserine on the outer leaflet of the plasma membrane, DNA fragmentation, and cell cycle arrest. epa.govnih.govfardislab.com

In Leishmania parasites, this compound triggers an apoptosis-like cell death cascade. oup.combioline.org.br Studies on Leishmania amazonensis and Leishmania donovani have demonstrated that exposure to this compound leads to the externalization of phosphatidylserine, a key marker of early apoptosis, and fragmentation of genomic DNA into oligonucleosome-sized fragments. bioline.org.brnih.gov Furthermore, this compound treatment causes a loss of mitochondrial membrane potential and the release of cytochrome c, which in turn activates cellular proteases and DNases, leading to the degradation of both nuclear and kinetoplast DNA. epa.gov

The induction of apoptosis by this compound is a dose- and time-dependent process. nih.govfardislab.com For instance, in L. tropica promastigotes, incubation with 24 µM this compound for 24 hours resulted in a significant increase in the sub-G0/G1 cell population, indicative of DNA fragmentation. nih.gov Similarly, in L. infantum, treatment with this compound led to a time-dependent increase in annexin-V positive cells, reaching 80% after 48 hours, signifying a high level of apoptosis. fardislab.comscielo.br

Cell Cycle Arrest

In addition to inducing apoptosis, this compound can arrest the cell cycle at various checkpoints, thereby inhibiting cell proliferation. This effect has been observed in both cancer cells and protozoan parasites. bioone.orgaacrjournals.org

In head and neck squamous carcinoma cells, perifosine, a structurally related alkylphospholipid, causes cell cycle arrest at the G1-S and G2-M boundaries. aacrjournals.org This arrest is associated with an increased expression of the p21WAF1 protein, a cyclin-dependent kinase inhibitor, independent of p53 function. aacrjournals.org Similar effects on the cell cycle, with accumulation of cells in the G1 and G2-M phases, have been observed with this compound. aacrjournals.org

In Leishmania species, this compound treatment leads to an accumulation of cells in the sub-G0/G1 phase, which is a hallmark of apoptotic cells with fragmented DNA. nih.govbioline.org.brnih.gov For example, in L. infantum promastigotes treated with this compound, the proportion of cells in the sub-G0/G1 phase increased from 3.22% in control cells to 16.5% after 24 hours and to 49% after 48 hours of exposure. scielo.br This arrest prevents the parasite from completing its cell division cycle, ultimately contributing to its demise.

Alterations in Lipid Metabolism

A significant aspect of this compound's mechanism of action is its ability to interfere with lipid metabolism and the integrity of cellular membranes. patsnap.comresearchgate.net As an alkylphosphocholine compound, this compound integrates into the lipid bilayer, altering membrane fluidity and disrupting crucial lipid-dependent signaling pathways. patsnap.com

In Leishmania parasites, this compound has been shown to perturb the biosynthesis of essential phospholipids. oup.comresearchgate.netnih.gov Transient treatment of L. donovani promastigotes with this compound resulted in a significant decrease in phosphatidylcholine (PC) levels and a corresponding increase in phosphatidylethanolamine (PE). researchgate.netnih.gov This is thought to be due to the partial inactivation of PE-N-methyltransferase, an enzyme involved in PC synthesis. researchgate.netnih.gov Furthermore, this compound treatment can lead to an increase in lysophosphatidylcholine, possibly through the activation of phospholipase A2. researchgate.netnih.gov

Interactive Data Tables

Table 1: Effect of this compound on Leishmania infantum Cell Cycle Progression

Data sourced from a study on L. infantum promastigotes treated with an IC50 dose of this compound. scielo.br

Table 2: Changes in Phospholipid Composition in Leishmania donovani Promastigotes after this compound Treatment

Data from transient treatment of L. donovani promastigotes with 10 μM this compound. researchgate.netnih.gov

Efficacy in Immunodeficient Patient Populations (e.g., HIV Co-infection)

Response in Refractory CL Cases

This compound is an approved treatment for cutaneous leishmaniasis (CL) wikipedia.org. However, clinical trials have documented instances of treatment failures and relapses, particularly in Latin America when addressing infections caused by Leishmania subgenus Viannia species asm.org. A study indicated that 40% of participants had received unsuccessful prior therapies before being treated with this compound for CL oup.com.

In a case series involving ten pediatric patients with CL, this compound treatment resulted in a complete response in 80% of cases, while 20% experienced treatment failure nih.gov. A comparative study focusing on Leishmania panamensis revealed this compound failure rates of 8.92%, in contrast to 22.03% for meglumine antimoniate nih.gov. Furthermore, a randomized controlled trial conducted in Brazil and Colombia, evaluating Leishmania panamensis and Leishmania guyanensis, demonstrated this compound to be non-inferior to meglumine antimoniate, with failure rates of 17.2% for this compound and 31% for meglumine antimoniate nih.gov. In some instances of Leishmania braziliensis CL, patients did not respond to this compound but eventually experienced spontaneous resolution ajtmh.org. For cases with partial response, prolonging the treatment duration from 6 weeks to 3 months proved effective in achieving a favorable outcome nih.gov.

Monotherapy Efficacy and Relapse Rates

Early studies on this compound monotherapy for PKDL (2008-2010) reported no relapses within a 12-month follow-up period plos.org. However, more recent reports indicate a significant increase in relapse rates, reaching up to 15% with this compound monotherapy nih.gov. In a study of 73 patients who completed this compound treatment, approximately 4% experienced relapse by 12 months, a figure that rose to 15% by 18 months plos.orginfontd.org.

Table 2: PKDL Relapse Rates with this compound Monotherapy

Skin Pharmacokinetics in PKDL Treatment

Understanding the distribution of antileishmanial compounds within human skin, the primary site of infection in PKDL, has been a knowledge gap dndi.orgresearchgate.net. A study investigated the skin distribution of this compound in 52 PKDL patients who received liposomal amphotericin B combined with this compound for 21 days dndi.orgresearchgate.net.

On day 22 of treatment, the median this compound concentrations were measured at 43.73 µg/g in skin tissue and 33.29 µg/mL in plasma researchgate.net. The median individual concentration ratio of this compound in skin to plasma was found to be 1.19 researchgate.net. Significantly, in 87% of the patients, the skin exposure to this compound surpassed the suggested EC90 pharmacokinetic target of 10.6 mg/L, which is associated with in vitro susceptibility researchgate.net. Simulations further indicated that the residence time of this compound in the skin would be more than twice as long as in plasma, with estimated mean residence times of 604 hours in skin versus 266 hours in plasma researchgate.net. These findings collectively demonstrate substantial exposure and prolonged retention of this compound within the skin, thereby supporting its utility in treating cutaneous manifestations of leishmaniasis dndi.orgresearchgate.net. A proof-of-concept study also validated dermal microdialysis as a minimally invasive technique for measuring dermal drug exposure in PKDL patients, confirming this compound's presence in both plasma and skin, consistent with its known extensive plasma and tissue accumulation medrxiv.org.

Free-Living Amebae Infections (e.g., Primary Amebic Meningoencephalitis)

This compound is utilized in the treatment of free-living amoeba (FLA) infections, which encompass primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri, and granulomatous amebic encephalitis (GAE) caused by Balamuthia mandrillaris and Acanthamoeba species wikipedia.orgdrugbank.comcdc.govvirginia.govnih.govpatient.infonih.govcdc.govnih.gov. It has been granted orphan drug status in the United States for acanthamoeba keratitis and PAM wikipedia.org.

Historically, PAM caused by Naegleria fowleri has been associated with an extremely high mortality rate, with only a handful of documented survivors in North America among a large number of confirmed infections wikipedia.orgcdc.govnih.govlivescience.com. However, in 2013, two children survived and recovered from PAM following treatment that included this compound wikipedia.orgcdc.govpatient.info. Another survivor was reported in 2016 cdc.gov. Laboratory studies have demonstrated this compound's ability to kill FLA, including Naegleria fowleri cdc.gov. The drug has also been successfully employed in treating patients infected with Balamuthia and disseminated Acanthamoeba infection cdc.govpatient.info. This compound is notable for its ability to penetrate the blood-brain barrier livescience.com.

For the treatment of PAM, a combination of medications is typically recommended, often comprising amphotericin B, azithromycin, fluconazole, rifampin, this compound, and dexamethasone cdc.govclevelandclinic.orgcdc.gov. While this compound has shown promise in these severe infections, some in vitro and animal model experiments have suggested that it may not be as potent as other drugs, such as chlorpromazine and diminazene aceturate wikipedia.org. It is important to note that the CDC no longer directly provides this compound for FLA infections, as the drug is now commercially available cdc.govvirginia.gov.

Table 3: this compound in Free-Living Amoebae Infections

Trypanosomiasis (e.g., Chagas Disease)

This compound (MLT) has emerged as a promising candidate for the treatment of Chagas disease, caused by the hemoflagellate Trypanosoma cruzi frontiersin.orgnih.gov. Current therapeutic options for Chagas disease, such as benznidazole (BZ) and nifurtimox (NFX), often present limitations including toxicity, low solubility, and reduced efficacy, especially in the chronic phase frontiersin.orgresearchgate.net. Research has explored this compound both as a monotherapy and in combination with existing drugs to enhance treatment outcomes.

In Vitro Efficacy: In vitro studies have demonstrated this compound's potent activity against different stages of Trypanosoma cruzi. For instance, a study evaluating the VD strain (DTU TcVI) showed that this compound exhibited an inhibitory concentration 50% (IC50) of 0.51 µM against amastigotes and a lethal concentration 50% (LC50) of 31.17 µM against trypomastigotes frontiersin.orgnih.gov.

Furthermore, studies investigating drug interactions using the fixed-ratio method indicated synergistic effects when this compound was combined with benznidazole against trypomastigotes (Sum of Fractional Inhibitory Concentrations (ΣFIC) = 0.45) and additive effects against amastigotes (ΣFIC = 0.71) frontiersin.orgnih.gov. This compound also demonstrated higher cytotoxic activity against Y-strain epimastigotes compared to benznidazole, with an IC50 of 3.5 ± 1 µg ml−1 (equivalent to 8 ± 1 µM) nih.gov. Notably, unlike benznidazole, this compound showed consistent susceptibility against both Y and Colombiana strains of T. cruzi epimastigotes, including drug-resistant variants nih.gov.

In Vivo Efficacy: Preclinical in vivo studies have supported this compound's potential. In a murine model of acute T. cruzi infection, this compound monotherapy exhibited a dose-dependent parasitostatic effect frontiersin.orgnih.gov. This effect was significantly enhanced when this compound was combined with benznidazole, effectively preventing parasitemia rebound even after a stringent immunosuppression protocol frontiersin.orgnih.gov.

Preliminary studies involving BALB/c mice infected with T. cruzi strain Y revealed that oral administration of this compound led to improved survival rates and a reduction in parasitemia levels comparable to those achieved with benznidazole nih.gov. Four months post-treatment, no parasites were detectable in the blood or spleen tissue sections of these mice maintained in culture nih.gov.

A recent study using Swiss mice infected with the Y strain of T. cruzi further highlighted the benefits of combination therapy. The research compared monotherapy with this compound or benznidazole to their combination.

The combination of 40 mg/kg this compound (administered orally for 10 consecutive or alternate days) with 50 or 100 mg/kg benznidazole (administered for 20 consecutive days) demonstrated superior efficacy compared to isolated treatments researchgate.net. Specifically, alternating administration of 40 mg/kg this compound with 50 mg/kg benznidazole resulted in a 62.5% cure rate, which was comparable to the efficacy of 100 mg/kg benznidazole alone researchgate.net. When 40 mg/kg this compound was combined with 100 mg/kg benznidazole, the cure rate increased to 87.5% with consecutive administration and reached 100% with alternating administration researchgate.net. Quantitative Polymerase Chain Reaction (qPCR) analyses confirmed a significant reduction in parasite DNA in cardiac and colonic tissues in the groups receiving combination therapy researchgate.net. These findings underscore the potential of this compound in improving Chagas disease treatment, particularly through combination strategies.

Antifungal Research

This compound is recognized as a promising repurposed drug for the treatment of various fungal infections nih.gov. Its antifungal activity has been demonstrated against a wide array of medically important fungi, including dermatophytes, Cryptococcus spp., Candida spp., Sporothrix spp., Paracoccidioides spp., Histoplasma capsulatum, Coccidioides posadasii, Rhizopus spp., Aspergillus spp., Fusarium spp., and Scedosporium spp. nih.govfrontiersin.org.

Mechanism of Antifungal Action: Research indicates that this compound exerts its antifungal effects by interacting with fungal lipids and affecting membrane integrity nih.gov. Studies on Mucorales species revealed that this compound treatment led to modifications in cell wall components, neutral lipids, mitochondrial membrane potential, and cell morphology, alongside the induction of oxidative stress nih.gov. The addition of purified ergosterol and glucosylceramide to the culture medium increased this compound's Minimum Inhibitory Concentration (MIC), suggesting its direct interaction with crucial fungal lipids nih.gov.

In Cryptococcus yeasts, this compound has been shown to increase plasma membrane permeability and reduce yeast viability asm.org. Exogenous ergosterol significantly reduced this compound's antifungal effect on Cryptococcus spp. (increasing MIC values up to 16-fold), further supporting the hypothesis that this compound directly interacts with ergosterol molecules in the fungal plasma membrane asm.org. This compound treatment also resulted in a reduced mucopolysaccharide capsule and altered mitochondrial ultrastructure in Cryptococcus asm.org.

Efficacy Against Biofilms: this compound has shown significant activity against fungal biofilms, which are often associated with drug resistance and chronic infections. It displayed activity against biofilms formed by various Mucorales species nih.gov.

Specific findings include:

Fusarium oxysporum and Candida albicans nail biofilms: this compound exhibited potent activity against biofilms of these species formed on human nail fragments in vitro microbiologyresearch.org.

For F. oxysporum, 8 µg ml−1 of this compound inhibited biofilm formation by 93%, and 256 µg ml−1 reduced the metabolic activity of pre-formed nail biofilms by 93% microbiologyresearch.org.

For C. albicans, 1000 µg ml−1 of this compound inhibited biofilm formation by 89% and reduced the metabolic activity of pre-formed biofilms by 99% microbiologyresearch.org.

Scanning Electron Microscopy (SEM) analyses confirmed a clear reduction in biofilm biomass following this compound treatment microbiologyresearch.org.

Efficacy Against Specific Fungal Pathogens:

Cryptococcus spp.: this compound is fungicidal against planktonic Cryptococcus spp. cells, though its effect is reduced against sessile biofilm cells asm.org. C. gattii generally shows less susceptibility than C. neoformans asm.org.

Aspergillus spp.: this compound has demonstrated effectiveness against azole-resistant Aspergillus isolates, with an MIC range of 1.562-6.25 µg/ml researchgate.net. The MIC50 and MIC90 concentrations were 1.562 µg/ml and 3.125 µg/ml, respectively researchgate.net. While this compound had a higher geometric mean MIC (2.459 µg/ml) for wild-type Aspergillus isolates compared to itraconazole (0.220 µg/ml) and voriconazole (0.298 µg/ml), there was no statistically significant difference in this compound MIC results between azole-resistant and azole-susceptible Aspergillus isolates researchgate.net.

Scedosporium and Lomentospora species: this compound is active against these species at concentrations of 2–4 µg/ml frontiersin.org. In S. aurantiacum, it induces plasma membrane disorganization, loss of membrane integrity, oxidative stress, and mitochondrial disturbances frontiersin.org.

These findings collectively highlight this compound's significant potential as an antifungal agent, particularly given its activity against drug-resistant strains and biofilms.

Resistance Mitigation

Nifuratel Combinations

Recent research has explored the potential of combining this compound with nifuratel, a nitrofurantoin derivative, for the treatment of visceral leishmaniasis. nih.govnih.gov Studies have demonstrated a potent synergistic effect between this compound and nifuratel against both axenic and intracellular amastigotes of Leishmania donovani. nih.govnih.govmdpi.com In vivo studies using a mouse model of visceral leishmaniasis have also shown promising results for this combination. nih.govnih.gov The rationale behind this combination is to leverage different mechanisms of action to improve therapeutic outcomes. nih.gov Nifuratel, originally identified as a promising repurposed drug from a collection of anti-infective agents, has shown potential against visceral leishmaniasis. nih.govnih.govresearchgate.net

The synergistic interaction between this compound and nifuratel has been observed in various experimental settings. nih.govmdpi.com In vitro and ex vivo experiments have confirmed this synergy, suggesting that the combination could lead to a reduction in the required doses of each drug, potentially minimizing side effects. nih.govmdpi.com

Other Synergistic Agent Research

Beyond nifuratel, research has investigated the synergistic potential of this compound with other compounds.

Paromomycin: The combination of this compound and paromomycin has been studied for treating visceral leishmaniasis. dndi.org While some in vitro studies have shown an indifferent interaction, in vivo studies have demonstrated a potentiation of this compound's activity when combined with paromomycin. nih.govnih.govplos.org The activity enhancement index (AEI) for this combination has been reported to be as high as 7.22. nih.govnih.gov

Amphotericin B: In vivo studies have revealed a significant potentiation of this compound's activity when combined with amphotericin B, with an AEI of up to 11.3. nih.govnih.gov However, in vitro interactions have been classified as indifferent. nih.govnih.gov A synergistic effect of this compound combined with amphotericin B has been observed against Candida krusei isolates, including both planktonic cells and biofilms. frontiersin.org

Sodium Stibogluconate: In vitro studies have indicated a synergistic to indifferent interaction when this compound is combined with sodium stibogluconate. nih.govnih.gov Conversely, in vivo studies have shown no significant interaction between the two drugs. nih.govnih.gov

Sitamaquine: In vitro research has demonstrated an indifferent interaction between this compound and sitamaquine. nih.govnih.gov

Amiodarone: Studies have shown that the combination of this compound and the antiarrhythmic drug amiodarone has synergistic effects against Leishmania mexicana intracellular amastigotes. asm.orgnih.gov In a murine model of cutaneous leishmaniasis, this combination led to a high rate of parasitological cure. asm.orgnih.gov

Apigenin: Combination therapy with this compound and the flavonoid apigenin has been explored for experimental cutaneous leishmaniasis, showing good clinical and parasitological responses at low doses. nih.gov

Pyrvinium Pamoate: Research has investigated the synergistic effect of pyrvinium pamoate in combination with this compound against Leishmania. mdpi.com

Table 1: In Vitro and In Vivo Interactions of this compound with Other Antileishmanial Drugs