Clofazimine

Targeting Mycobacterial Integration Host Factor (mIHF)

Emerging research indicates that clofazimine targets the mycobacterial integration host factor (mIHF) in Mycobacterium tuberculosis. biorxiv.org mIHF is a vital nucleoid-associated protein that plays a critical role in maintaining DNA integrity, organizing the chromosome, and regulating gene expression in mycobacteria. biorxiv.org Studies have demonstrated that this compound binds to mIHF, thereby inhibiting its ability to bind DNA and consequently disrupting mycobacterial gene expression. biorxiv.org This interaction with a fundamental DNA-associated protein represents a potentially unique mechanism among existing antibiotics and may contribute to this compound's distinct activity against Mycobacterium tuberculosis. biorxiv.org

Role of Iron Homeostasis and Mycobactin Interaction

Iron acquisition is essential for the survival and virulence of mycobacteria within the host. Mycobacteria produce siderophores, such as mycobactin, to chelate and transport iron. researchgate.netmdpi.com While the precise interaction between this compound and mycobacterial iron homeostasis or mycobactin was not extensively detailed in the provided search results, the critical role of iron uptake pathways in mycobacterial survival suggests that interference with these processes could represent a potential mechanism by which this compound exerts its effects. Mycobactin is a specific type of hydroxamate siderophore produced by mycobacteria. researchgate.netmdpi.com

Inhibition of T-Lymphocyte Activation and Proliferation

A significant aspect of this compound's immunomodulatory effect is its ability to inhibit the activation and proliferation of T lymphocytes. nih.govdrugbank.comoup.com This inhibitory effect has been observed in in vitro studies at concentrations relevant to therapeutic levels achieved during leprosy treatment. oup.com The suppression of T-lymphocyte activity is mediated through multiple pathways. drugbank.comoup.com

Direct Antagonism of T-cell Kv1.3 Potassium Channels

This compound has been identified as a direct antagonist of Kv1.3 potassium channels found on T cells. drugbank.comoup.com Kv1.3 channels are voltage-gated ion channels that are critical for maintaining the membrane potential and regulating calcium signaling in activated T lymphocytes. oup.com By blocking these channels, this compound disrupts potassium efflux, which in turn impairs the membrane repolarization required for sustained calcium influx through calcium release-activated Ca2+ (CRAC) channels. oup.com Altered calcium signaling can suppress the activity of the calcineurin-NFAT pathway, a signaling cascade essential for the transcription of the interleukin-2 (IL-2) gene. oup.comresearchgate.net Reduced IL-2 production contributes to the inhibition of T-cell proliferation. oup.comresearchgate.net

Promotion of E-series Prostaglandin and Reactive Oxygen Species Release from Neutrophils and Monocytes

This compound can indirectly suppress T-cell proliferation by stimulating the release of E-series prostaglandins, particularly prostaglandin E2 (PGE2), and reactive oxygen species (ROS) from neutrophils and monocytes. oup.comoup.com In mixed leukocyte cultures, this compound promotes the release of these molecules from bystander phagocytes. oup.comoup.com PGE2, derived from arachidonic acid via cyclooxygenase, can activate EP2 receptors on T cells, leading to increased intracellular cAMP levels, which are known to inhibit T-cell proliferation. oup.com ROS produced by phagocytes, often through the activation of NADPH oxidase by arachidonic acid, can also non-specifically interfere with T-cell proliferation. oup.com Studies have demonstrated that this compound treatment enhances PGE2 production by macrophages, and PGE2 is known to suppress T-cell proliferation. asm.org

Myeloperoxidase System Inhibition

This compound has been shown to inhibit the myeloperoxidase (MPO) system. nih.govafricaresearchconnects.com MPO is a heme enzyme predominantly found in neutrophils and monocytes, where it plays a key role in innate immunity and inflammation by generating potent oxidants, such as hypochlorous acid (HOCl), from hydrogen peroxide and chloride ions. nih.govnih.gov Research indicates that this compound inhibits the MPO system by scavenging the chlorinating oxidants produced. nih.govafricaresearchconnects.com Studies have demonstrated that this compound inhibits the chloride-stimulated oxidation of NADH, a reaction catalyzed by MPO. nih.govafricaresearchconnects.com Furthermore, this compound was found to be a more effective scavenger of HOCl compared to dapsone. nih.govafricaresearchconnects.com This ability to neutralize MPO-derived oxidants is believed to contribute to this compound's anti-inflammatory properties. nih.govafricaresearchconnects.com

Here is a summary of some of the research findings discussed:

Modulation of Cytokine Production (e.g., IL-2, IL-1 Receptor Antagonist)

This compound has been shown to influence the production of various cytokines, playing a role in its anti-inflammatory and immunomodulatory effects. Studies have indicated that this compound can inhibit the production of IL-2 in T cells. Research using Jurkat T cells demonstrated that this compound inhibits IL-2 proximal promoter-driven luciferase stimulated by PMA/ionomycin with an IC50 of 21.8 ± 4.4 nM. It also inhibited the activation of the endogenous IL-2 promoter in response to PMA and thapsigargin with an IC50 of 1.10 ± 0.26 µM. Furthermore, this compound inhibited human mixed lymphocyte reaction with an IC50 of 0.90 ± 0.17 µM, similar to its effect on endogenous IL-2 production in Jurkat T cells. researchgate.netnih.govplos.org The transcription activation of the IL-2 promoter is dependent on key transcription factors including NFAT, NF-κB, and AP-1. researchgate.netnih.gov this compound has been shown to inhibit the NFAT pathway in Jurkat T cells with an IC50 of 113 ± 30 nM. researchgate.netplos.org

In addition to inhibiting pro-inflammatory cytokines like IL-2, this compound has been observed to increase the levels of the interleukin-1 receptor antagonist (IL-1RA). mdpi.comresearchgate.net This increase in IL-1RA contributes to its anti-inflammatory properties. mdpi.comasm.org Studies in mice have shown dramatic increases in tissue inhibitor matrix metalloproteinase 1 (TIMP-1) and IL1-RA (538% and 346% increases, respectively) following this compound treatment, alongside a modest increase in TNF-alpha (83%) and several other pro- and anti-inflammatory cytokines. mdpi.com

Conversely, some studies suggest this compound treatment can enhance the levels of certain cytokines. In a study involving BCG revaccination in mice, this compound treatment significantly enhanced the levels of IL-2, TNF-α, IFN-γ, IL-12, and IL-6, while decreasing the levels of IL-10. nih.gov There was also a stable maintenance of IL-1β levels. nih.gov The enhancement in IL-2, TNF-α, and IFN-γ levels corroborated the finding that this compound treatment enhances the levels of polyfunctional memory T cells. nih.gov The increased level of IL-6 suggested that this compound treatment establishes a cytokine milieu that promotes Th17 cell generation. nih.gov

The modulation of cytokine production by this compound appears to be concentration and context-dependent, contributing to both its immunosuppressive and potentially immunostimulatory effects in different settings.

Here is a summary of this compound's effects on certain cytokines:

Suppression of Pathogenic Th17 Cells

This compound has been shown to impact Th17 cells, a subset of T helper cells involved in inflammatory responses and implicated in autoimmune diseases and immune-related adverse events. When combined with immune checkpoint blockade (ICB), this compound decreased the numbers and pathogenicity of intestinal Th17 cells in an E2F-dependent manner. aacrjournals.orgresearchgate.nethoustonmethodist.org This suppression of pathogenic Th17 cells may contribute to the ability of this compound to reduce immune-related adverse events associated with dual ICB therapy. aacrjournals.orghoustonmethodist.org

However, it is worth noting that one study in mice suggested that this compound treatment, through increased IL-6 levels, might establish a cytokine milieu that promotes Th17 cell generation in the context of BCG revaccination. nih.gov This highlights the complex and context-dependent effects of this compound on different T cell subsets.

Modulation of Macrophage Activity and Apoptosis Induction

This compound significantly influences macrophage activity, including the induction of apoptosis. Studies have demonstrated that this compound exhibits apoptosis-inducing activity in macrophages. asm.orgresearchgate.netnih.gov When human monocyte-derived macrophages were cultured in vitro with this compound, they showed decreased metabolic activity, cell shrinkage, nuclear condensation, and fragmentation, all indicative of cell death. asm.orgnih.gov The endonuclease inhibitor ZnCl2 inhibited this this compound-induced cell death. asm.orgnih.gov

A significant enhancement of caspase-3 activity has been observed in this compound-treated macrophages and THP-1 cells, suggesting that this compound induces apoptosis via caspase-3 pathways in these cells. asm.orgresearchgate.netnih.gov This apoptosis-inducing activity in macrophages may also contribute to the antibacterial properties of this compound. asm.org

However, the effect of this compound on macrophage apoptosis can be influenced by its physical form. While the dissolved fraction of this compound was found to be cytotoxic and induced apoptosis in macrophages in vitro, in vivo, the formation of crystal-like drug inclusions (CLDIs) within macrophages did not induce macrophage apoptosis. oncotarget.com Instead, CLDIs altered immune signaling pathways downstream of Toll-like receptor (TLR) ligation, leading to decreased NF-κB activation and TNFα production and enhanced IL-1RA production. oncotarget.com This suggests that in vivo, macrophages may detoxify soluble this compound by sequestering it in an insoluble form, which contributes to the drug's anti-inflammatory activity rather than inducing apoptosis. oncotarget.com

Impact on Chromatin Accessibility and E2F1-TCF1 Pathway in T-cells

This compound has been shown to impact T-cells by altering chromatin accessibility and influencing the E2F1-TCF1 pathway. Mechanistically, this compound was found to alter chromatin accessibility in CD8+ T cells. aacrjournals.orgnih.gov This alteration leads to the expression of E2F/E2F1 target genes associated with early memory T-cell differentiation, including Tcf7. aacrjournals.orgnih.gov this compound treatment stimulated E2F1 binding to the Tcf7 promoter and boosted the CD8+ T-cell antitumor response. aacrjournals.org Repressing E2F1 signaling through overexpression of constitutively active aryl hydrocarbon receptor or knockout of E2f1 or Tcf7 decreased tumor cell killing by this compound. aacrjournals.org

The enhancement of E2F1 transcriptional activity by this compound induces Tcf7 promoter activation and increases Tcf1 expression. researchgate.net This amplification of the E2F1-TCF1 pathway in CD8+ T cells contributes to the tumor-inhibiting potency of cytotoxic T lymphocytes. researchgate.net Furthermore, this mechanism is also linked to the reduction of pathogenic Th17 differentiation, which helps to attenuate immune-related adverse events. researchgate.nethoustonmethodist.org

Changes in chromatin accessibility, including the opening of chromatin around the Tcf7 locus and closing of the Pdcd1 locus, were observed in tumor-infiltrating CD8+ T cells following this compound treatment. nih.gov Gene set enrichment analysis (GSEA) also indicated that this compound combined with ICB skewed tumor-specific T cell differentiation toward early memory T cell development. nih.gov

Inhibition of the Wnt Signaling Pathway

This compound has been identified as a specific inhibitor of the canonical Wnt signaling pathway. unil.chnih.govunil.chasm.orgresearchgate.netmdpi.com This pathway is frequently overactivated in various cancers and plays a crucial role in oncogenic transformation and progression. nih.govmdpi.com

Studies have shown that this compound inhibits canonical Wnt signaling in a panel of triple-negative breast cancer (TNBC) cells in vitro. unil.chunil.ch It suppresses the canonical Wnt pathway, both endogenous and exogenously induced, as measured by the expression of Axin2, c-Myc, and TopFlash reporter genes/constructs, as well as by monitoring cytoplasmic β-catenin levels. unil.ch this compound has also been shown to inhibit Wnt signaling in other cancer types, including hepatocellular carcinoma (HCC), colorectal cancer (CRC), and ovarian cancer cell lines in a dose-dependent manner. nih.govresearchgate.net The efficacy of this compound against a given cancer type can correlate with the basal levels of Wnt pathway activation and the drug's ability to inhibit Wnt signaling in that cancer. nih.gov

In vivo studies using mouse xenograft models of TNBC have shown that this compound efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. unil.chnih.govjapsonline.comresearchgate.net This inhibition involves blocking β-catenin accumulation in the cytoplasm of tumor cells, effectively switching the Wnt pathway from an "on" to an "off" state. unil.ch Additionally, a reduction in the Wnt target gene MDR-1 has been observed upon this compound treatment. unil.ch

This compound targets the Wnt pathway downstream of β-catenin and can inhibit the proliferation of TNBC cells. mdpi.com Its anti-Wnt effect has been observed with an IC50 in the low-µM range (~3 µM). mdpi.com

Induction of Apoptosis via Caspase-3 Pathways

This compound induces apoptosis in various cancer cell lines, and this process often involves the activation of caspase-3. Studies have shown that this compound treatment leads to increased caspase-3 activity in macrophages and THP-1 cells, indicative of apoptosis induction. asm.orgresearchgate.netnih.gov

In the context of cancer, this compound has been shown to induce apoptosis in chronic myeloid leukemia (CML) cells. haematologica.orgresearchgate.net this compound induced cytochrome C release and activated caspase-3 and caspase-9, but not caspase-8, suggesting mitochondria-mediated apoptosis. haematologica.orgresearchgate.net This was consistent with decreased B-cell lymphoma 2 (BCL-2) and increased BAX expression. haematologica.orgresearchgate.net

This compound also induces apoptosis in pancreatic ductal adenocarcinoma (PDAC) cell lines. oncotarget.comnih.gov Evidence suggests that this compound induces apoptosis in PDAC cells with an EC50 in the µM range, potentially via its inhibitory action on the potassium channel Kv1.3. oncotarget.comnih.gov Inhibition of mitochondrial Kv1.3 (mtKv1.3) increases mitochondrial ROS production, which appears necessary for triggering programmed cell death. oncotarget.com

Furthermore, this compound treatment has been shown to induce cytotoxicity and caspase-dependent apoptosis in prostate cancer cell lines. medrxiv.org Mechanistic assays in multiple myeloma cell lines treated with this compound revealed mitochondrial membrane depolarization, changes in cell membrane asymmetry, and increased caspase-3 activity, indicating an intrinsic apoptosis mechanism. researchgate.netnih.gov

The induction of apoptosis via caspase-3 pathways is a key mechanism by which this compound exerts its anti-cancer effects across different cancer types.

Mitochondrial Membrane Depolarization

Studies have indicated that this compound can induce mitochondrial membrane depolarization. In prostate cancer cell lines, this compound treatment has been shown to result in mitochondrial membrane depolarization. medrxiv.orgmedrxiv.org This effect has also been observed in macrophages treated with soluble this compound, where it correlated with decreased mitochondrial staining and morphological signs of apoptosis. nih.gov Furthermore, in chronic myeloid leukemia (CML) cells, this compound induced mitochondrial membrane depolarization, alongside increased reactive oxygen species (ROS) production. nih.gov Changes in mitochondrial membrane permeability, such as those leading to altered staining patterns, are considered upstream events in the activation of apoptosis pathways. nih.gov

Enhancement of CD8+ T-cell Cytotoxic Activity

Research suggests that this compound can enhance the cytotoxic activity of CD8+ T cells. This enhancement has been observed in the context of cancer immunotherapy. This compound has been shown to activate the E2F1 pathway in CD8+ T cells, which may improve the ability of these "killer cells" to recognize and respond to tumors. houstonmethodist.org Mechanistic studies using single-cell RNA sequencing and other techniques have indicated that a combination of this compound and dual immune checkpoint blockade induced a transcriptional signature in tumor-infiltrating CD8+ T cells characterized by cytotoxic and early-memory features, with upregulation of genes like Tcf7, Lef1, Gzmb, and Ifng, and downregulation of exhaustion markers. williamscancerinstitute.com This suggests that this compound helps immune cells maintain their ability to effectively respond to cancer over time. williamscancerinstitute.com

Modulation of Tumor Microenvironment (e.g., M1-like Macrophages, Myeloid-Derived Suppressor Cells)

This compound has demonstrated the ability to modulate the tumor microenvironment (TME), influencing the behavior of immune cells within it. Studies have shown that this compound can increase the percentage of M1-like macrophages and monocytic myeloid-derived suppressor cells (MDSCs) in the TME. nih.gov M1 macrophages are generally associated with immunostimulatory and antitumor functions, releasing cytokines and chemokines that can directly kill tumor cells and augment the activity of T cells. thno.org Conversely, MDSCs are a heterogeneous population of immature immune cells known for their potent immunosuppressive effects on T cell proliferation and activity, contributing to tumor growth and T cell dysfunction. frontiersin.org In glioblastoma models, this compound modulated the TME by increasing the infiltration of cytotoxic CD8+ T cells and altering macrophage polarization towards a pro-inflammatory M1 phenotype, while also reducing regulatory T cells (Tregs). nih.govresearchgate.net Tregs are another type of immunosuppressive cell found in the TME that can limit anti-tumor immune responses. nih.gov

Impact on Cancer Cell Growth and Survival in Specific Cell Lines

This compound has shown an impact on the growth and survival of various cancer cell lines. Pre-clinical tests have indicated that this compound can reduce cancer cell growth and survival in some cancer cell lines, including those from colorectal, liver, ovarian, and brain tumors. unige.ch Its effects appeared to be more pronounced in cell lines where the Wnt signaling pathway was more strongly overactivated. unige.ch In triple-negative breast cancer (TNBC) cell lines, this compound suppressed cell proliferation and clonogenicity, inducing apoptosis and cell cycle arrest. unil.ch In pancreatic ductal adenocarcinoma (PDAC) cell lines harboring p53 mutations, this compound efficiently killed cells in vitro with an EC50 in the µM range, providing evidence that it induces apoptosis. nih.govresearchgate.net Studies in prostate cancer cell lines have also shown that this compound induces cytotoxicity and caspase-dependent apoptosis. medrxiv.orgmedrxiv.org

Below is a table summarizing some of the observed effects of this compound on cancer cell lines:

Reduction of PolyQ Protein Toxicity

Studies suggest that this compound can reduce the toxicity associated with polyQ proteins, which are found in patients with certain hereditary neurodegenerative diseases like Huntington's disease. ki.sescilifelab.se A high-throughput chemical screen identified this compound as a compound that lowers the toxicity of a protein containing an expanded polyQ repeat in in vitro and in vivo models, including zebrafish and neuron-specific worm models of polyQ disease. nih.govnih.govcore.ac.ukcsic.essemmelweis.huresearchgate.net

Restoration of Mitochondrial Function

This compound's beneficial effects in polyQ diseases appear to be linked to the restoration of mitochondrial function. ki.sescilifelab.se Computational analyses have indicated that this compound's effect in reducing polyQ toxicity is due to the stimulation of mitochondrial biogenesis, a process mediated by peroxisome proliferator-activated receptor gamma (PPARγ). nih.govnih.govcore.ac.ukcsic.essemmelweis.huresearchgate.net In agreement with these findings, this compound was shown to rescue mitochondrial dysfunction triggered by the expression of a polyQ-expanded protein. nih.govnih.govcore.ac.ukcsic.essemmelweis.huresearchgate.net This supports the hypothesis that polyQ diseases are associated with mitochondrial dysfunction and that stimulating mitochondrial biogenesis could be a therapeutic strategy. ki.senih.govcsic.es

Role of Cytochrome P450 Isoenzymes (e.g., CYP1A2, CYP3A4/A5)

Cytochrome P450 (CYP) isoenzymes play a role in the oxidative metabolism of this compound. Specifically, CYP1A2 is primarily involved in the formation of hydrolytic-dehalogenated this compound, while CYP3A4/A5 are responsible for the formation of hydrolytic-deaminated this compound. asm.orgresearchgate.netnih.gov CYP1A2 and CYP3A enzymes are broadly involved in the formation of oxidative metabolites. asm.orgresearchgate.netnih.gov In vitro studies have indicated that this compound can act as a weak inducer of CYP3A4 at low concentrations but inhibits CYP3A4 at therapeutic concentrations, suggesting potential for auto-induction and clinically significant interactions with drugs metabolized by CYP3A4. frontiersin.orgresearchgate.netresearchgate.net However, some clinical studies have not found a significant impact of this compound on the clearance of CYP3A4 substrates like bedaquiline. frontiersin.org

Glucuronidation and Sulfate Conjugation

Conjugation reactions, specifically glucuronidation and sulfate conjugation, are also involved in this compound metabolism. wikipedia.orgasm.orgresearchgate.netnih.gov Glucuronide conjugates are formed from oxidative metabolites. asm.orgresearchgate.netnih.gov UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of hydroxylated and hydrated this compound glucuronide include UGT1A1, UGT1A3, and UGT1A9. asm.orgresearchgate.netnih.gov Hydrolytic-deaminated this compound glucuronide is catalyzed by UGT1A4, UGT1A9, UGT1A3, and UGT2B4. asm.orgresearchgate.netnih.gov

Drug-Drug Interactions (DDIs) with Other Antimycobacterial Agents

Studies have investigated the potential for pharmacokinetic interactions between this compound and other antimycobacterial agents used in the treatment of leprosy and tuberculosis. While this compound is often used in combination regimens to prevent resistance and enhance efficacy, understanding these interactions is crucial. drugbank.commdpi.com

In the context of leprosy, this compound has been used in combination with dapsone and rifampicin. mdpi.com Some evidence suggests that this compound, when combined with rifampicin alone or with dapsone, can delay the time to reach peak serum rifampicin concentration and decrease its absorption rate. inchem.org There is no evidence of interference between this compound and dapsone regarding their antimycobacterial activity, although in vitro studies showed opposite effects on neutrophil motility and lymphocyte transformation, potentially decreasing or nullifying the anti-inflammatory effects of dapsone. inchem.org

For drug-resistant tuberculosis, this compound is a key component of treatment regimens. oup.comfrontiersin.org A secondary analysis of an observational study assessed the interaction between this compound and bedaquiline, another crucial DR-TB drug. This study found no significant pharmacokinetic interaction between this compound and bedaquiline, indicating that their combination is safe in terms of pharmacokinetics for treating MDR-TB. mdpi.comhivglasgow.org this compound did not significantly impact the bioavailability of bedaquiline or its metabolite M2. mdpi.comhivglasgow.org

Research has also explored interactions between this compound and other agents frequently used for DR-TB, including isoniazid, linezolid, levofloxacin, and cycloserine (dosed as terizidone). asm.orgresearchgate.net One study found that the addition of this compound to a DR-TB regimen resulted in a statistically significant 15% reduction in levofloxacin clearance, leading to a 19% increase in levofloxacin AUC. asm.orgresearchgate.net While the precise mechanism for this interaction is not fully elucidated, in vitro studies suggest this compound may inhibit P-glycoprotein and BCRP, which are involved in the renal tubular secretion of levofloxacin. asm.org No significant effect on the pharmacokinetics of high-dose isoniazid, linezolid, or cycloserine was observed in this study. asm.orgresearchgate.net

This compound's potential to inhibit certain cytochrome enzymes, particularly CYP3A4/A5, has been noted in in vitro studies. frontiersin.orgnih.govresearchgate.net This could lead to potential pharmacokinetic drug-drug interactions with co-administered drugs metabolized by these enzymes. frontiersin.orgresearchgate.net While one study did not find a significant difference in the clearance of bedaquiline (a CYP3A4 substrate) or its metabolite when co-administered with this compound, this compound was predicted to be a moderate to strong inhibitor of CYP3A4/5 and a weak inhibitor of CYP2C8 and CYP2D6 based on static and PBPK modeling. frontiersin.orgresearchgate.net

Interaction with Efflux Pumps (e.g., P-glycoprotein, BCRP)

In vitro studies have indicated that this compound interacts with several membrane transporters, including efflux pumps like P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), as well as uptake transporters such as Organic Anion Transporter 1 (OAT1) and Organic Anion Transporter 3 (OAT3). asm.orgnih.govresearchgate.netnih.gov

This compound has been identified as a substrate of P-gp and BCRP. asm.orgnih.govresearchgate.netnih.gov In vitro experiments using cell lines overexpressing these transporters have demonstrated that this compound is effluxed by both P-gp and BCRP. asm.orgnih.govresearchgate.netnih.gov The presence of selective inhibitors of P-gp (e.g., verapamil, cyclosporine-A, PSC-833, quinidine) and BCRP (e.g., Ko143, daunorubicin) significantly increased the intracellular accumulation of this compound. asm.orgresearchgate.netnih.govresearchgate.netnih.gov Bidirectional transport assays showed mean efflux ratios for this compound of 4.17 ± 0.63 in P-gp overexpressing cells and 3.37 ± 1.2 in BCRP overexpressing cells. asm.orgresearchgate.netnih.govresearchgate.netnih.gov Kinetic studies estimated the Km and Vmax values for this compound transport by P-gp and BCRP. asm.orgresearchgate.netnih.govresearchgate.netnih.gov

These interactions suggest that P-gp and BCRP play a role in the disposition of this compound. asm.orgnih.gov As these transporters are expressed in the apical membrane of intestinal cells, they may influence the absorption of this compound. nih.gov Their presence at the blood-brain barrier may also contribute to the low concentrations of this compound observed in the brain. asm.orgnih.gov Furthermore, the inhibition of P-gp and BCRP by this compound, as suggested by in vitro research, could lead to drug-drug interactions with co-administered medications that are substrates for these transporters. mdpi.comasm.orgnih.gov For instance, the observed reduction in levofloxacin clearance when co-administered with this compound may be related to this compound's potential inhibition of P-gp and BCRP in the kidneys, affecting levofloxacin's tubular secretion. asm.org

The interaction of this compound with efflux pumps highlights the complexity of its pharmacokinetics and the potential for transporter-mediated drug-drug interactions, particularly in multi-drug regimens used for conditions like tuberculosis. asm.orgnih.gov

Data Tables

Mutations in Rv0678 Gene and Upregulation of Efflux Pumps (e.g., MmpL5, MmpS5)

A prominent mechanism of this compound resistance in M. tuberculosis involves mutations in the Rv0678 gene frontiersin.orgasm.orgfrontiersin.org. Rv0678 encodes a transcriptional repressor that regulates the expression of the mmpS5-mmpL5 operon, which codes for the MmpS5-MmpL5 efflux pump frontiersin.orgbiorxiv.orgplos.org. Mutations or insertions in Rv0678 can lead to impaired repressor function, resulting in the upregulation of the MmpS5-MmpL5 efflux pump frontiersin.orgplos.orgresearchgate.net. This increased expression of the efflux pump facilitates the active extrusion of this compound from the bacterial cell, thereby reducing its intracellular concentration and conferring resistance plos.orgresearchgate.netnih.gov. Studies have documented that mutations in Rv0678 can lead to a 2- to 4-fold increase in the minimum inhibitory concentration (MIC) of this compound in murine isolates and a 2- to 16-fold increase in bedaquiline MIC in clinical isolates frontiersin.org. A significant proportion of genomic variants causing elevated this compound and/or bedaquiline MICs affect the transcriptional repressor Rv0678 biorxiv.org. Structural modeling of Rv0678 suggests that resistance can arise from mechanisms such as impairment of DNA binding, reduction in protein stability, disruption of protein dimerization, and alteration in affinity for its fatty acid ligand biorxiv.org.

Impact on Membrane Potential and Potassium Uptake

This compound is known to interact with bacterial membrane phospholipids, potentially leading to membrane dysfunction frontiersin.orgnih.gov. One proposed mechanism of action involves the almost complete inhibition of potassium uptake by this compound through lysophosphatidic-mediated membrane dysfunction nih.govresearchgate.net. This interference with membrane potential can reduce ATP levels in M. tuberculosis nih.gov. While this is primarily described as a mechanism of drug action, alterations in membrane potential or potassium uptake systems could potentially contribute to resistance, although specific resistance mechanisms directly linked to these effects are less characterized compared to efflux pump mechanisms. Studies have investigated the effects of this compound on potassium uptake by M. tuberculosis, including Trk-deletion mutants, showing inhibition of rubidium-86 uptake researchgate.net. This compound has also demonstrated inhibitory effects on the activity of Na+,K+-ATPase in rat cardiomyocytes, highlighting its impact on ion transporters mdpi.com.

Cross-Resistance with Other Antimycobacterial Drugs (e.g., Bedaquiline)

A significant concern regarding this compound resistance is the observed cross-resistance with bedaquiline, another crucial drug for treating drug-resistant TB frontiersin.orgnih.gov. This cross-resistance is primarily mediated by mutations in the Rv0678 gene, which lead to the upregulation of the MmpS5-MmpL5 efflux pump, capable of extruding both drugs plos.orgresearchgate.netnih.gov. Cross-resistance between this compound and bedaquiline due to mutations in Rv0678, Rv1979c, and pepQ genes has been reported frontiersin.orgnih.gov. The emergence of such cross-resistance can limit treatment options for patients with multidrug-resistant and extensively drug-resistant TB frontiersin.orgnih.gov. Studies have shown that a high percentage of this compound-resistant isolates are also resistant to bedaquiline, particularly when the this compound MIC is elevated frontiersin.org. Cross-resistance between bedaquiline and this compound was reported in a certain percentage of MDR-TB and pre-XDR-TB/XDR-TB populations in a surveillance study shea-online.org.

Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB)

Clofazimine has demonstrated activity against Mycobacterium tuberculosis, including multidrug-resistant strains, in in vitro studies. ersnet.org Its repurposing for drug-resistant tuberculosis (DR-TB) is supported by evidence of potent activity against DR-TB strains in vitro and in mice, and a reported treatment-shortening effect in DR-TB patients as part of multidrug regimens. frontiersin.org

Clinical experience with this compound in tuberculosis has been reported. A large cohort study from Bangladesh described a standardized treatment regimen including this compound as being highly effective against MDR-TB. nih.govmdpi.com In this study involving 515 MDR-TB patients who received a this compound-containing regimen for a minimum of 9 months, 84.5% (435/515) had successful treatment outcomes. mdpi.com 93% of patients achieved culture conversion at month 2 of treatment, and 84.4% had a bacteriologically favorable outcome. mdpi.com Furthermore, 82.3% of patients did not relapse for 24 months after treatment completion. mdpi.com

A study involving 32 consecutive patients with MDR-TB treated with this compound-containing regimens reported a culture conversion rate of 53.1% (17/32). ersnet.org The treatment success rate was 48.4% (15/31). ersnet.org Factors associated with treatment success included male gender and concurrent use of linezolid. ersnet.org

This compound has been re-classified by the WHO from a Group 5 agent (drugs with unclear significance) to a Group B agent (drugs with second highest priority for use) for use in individualized DR-TB regimens, solidifying its role as a key drug in DR-TB therapy. frontiersin.org

Data Table: this compound in MDR-TB and XDR-TB Treatment Outcomes

Non-Tuberculous Mycobacterial (NTM) Infections

This compound is being investigated for its potential in treating various non-tuberculous mycobacterial (NTM) infections. clinicaltrials.eu NTM diseases are increasing in prevalence and represent a significant health issue. nih.gov Treatment of NTM diseases often requires multidrug regimens with long durations and can have poor cure rates. oup.com this compound has shown promise in treating NTM infections, particularly in cases of intolerance to first-line drugs or drug resistance. clinicaltrials.eu

In vitro studies have shown that rapidly growing mycobacteria were susceptible to this compound. nih.gov Large in vitro studies of this compound against rapidly growing mycobacteria (RGM) isolates have shown promising results. nih.gov For instance, one study reported a Minimum Inhibitory Concentration (MIC) of <1 µg/mL in 180 isolates of M. abscessus group, M. fortuitum, and Mycobacterium chelonae and noted synergism between this compound and amikacin. nih.gov Another study found that 97% of 564 isolates of 21 species of RGM had an MIC <1 µg/mL and also observed synergism between this compound and amikacin. nih.gov this compound has been found to have the lowest MIC50 among seven antibiotics studied on 67 isolates of M. abscessus group and noted synergism between this compound and tigecycline. nih.gov

Data Table: In Vitro Activity of this compound Against RGM

Mycobacterium avium Complex (MAC)

This compound has been evaluated in the treatment of MAC lung disease and bacteremia. nih.gov Clinical results have been inconsistent, although additional clinical trials are underway. nih.gov this compound is highly active in vitro against clinically important NTM species, including Mycobacterium avium complex (MAC), and shows synergy with clarithromycin and amikacin. oup.comoup.com

A retrospective study conducted in Canada evaluated treatment outcomes of a this compound-containing regimen in patients with MAC-pulmonary disease (MAC-PD). e-emj.org Among 107 patients, 90 received a regimen of this compound, macrolide, and ethambutol. e-emj.org All 90 patients (100%) treated with this compound achieved sputum culture conversion, compared to 71% (10/14) in the rifampin group (P=0.0002). e-emj.org Microbiological relapse occurred in 49% (52/107) of patients, with no significant difference between the groups. e-emj.org

Another retrospective study from Korea assessed the outcomes of a this compound-containing regimen in severe MAC-PD. oup.come-emj.org Among 170 patients, 71.2% had cavitary disease. oup.com Within 6 months, 45.3% (77/170) achieved culture conversion, and 54.6% (84/154) attained microbiological cure. oup.com The dose of this compound (100 mg vs 50 mg) was not associated with culture conversion or microbiological cure. oup.com The microbiological cure rate reached 71.0% when this compound was administered for 6–12 months, compared to 23.1% when administered for <6 months. oup.com

A large-scale meta-analysis evaluating treatment outcomes of individuals diagnosed with MAC and treated with a this compound-based regimen compared to non-clofazimine regimens found that the pooled treatment success rates were 56.8% in this compound groups and 67.9% in non-clofazimine groups. nih.gov However, success rates were higher (58.7%) in the treatment of HIV patients with disseminated infection within the this compound group. nih.gov

Research in a murine model of chronic progressive MAC-pulmonary infection compared a standard regimen (macrolide, ethambutol, and rifampicin) with an alternative regimen (replacing rifampicin with this compound). frontiersin.org The this compound-containing regimen provided significantly improved treatment efficacy, with greater efficacy after 2 weeks of treatment than after 4 weeks of treatment with the standard regimen, by rapidly reducing bacterial loads and lung inflammation. frontiersin.org

Data Table: this compound in MAC-PD Treatment Outcomes

Mycobacterium abscessus Group

Infections caused by the Mycobacterium abscessus group are challenging to treat due to high virulence, antibiotic resistance, and the lack of effective therapies. nih.gov this compound holds promise as a chemotherapeutic for the treatment of RGM, including the M. abscessus group. nih.gov

In vitro studies have shown this compound to be active against M. abscessus group isolates and demonstrated synergism with amikacin and tigecycline. nih.gov this compound can prevent the regrowth observed when amikacin or clarithromycin is used alone against M. abscessus. nih.gov

A retrospective review examined the clinical, radiographic, and microbiologic outcomes of patients with M. abscessus group lung disease who received this compound as part of an initial or salvage multidrug regimen. nih.gov After 12 months of a this compound-containing regimen, 81% of patients exhibited treatment response based on symptomatic improvement, 31% demonstrated radiographic improvement, and 24% achieved sputum-negative culture conversion. nih.gov

This compound is considered a first-line oral antibiotic for the treatment of M. abscessus-pulmonary disease (MAB-PD). oup.com

Studies in animal models have also investigated this compound against M. abscessus. In fly models, this compound extended the lifespan of Drosophila infected with M. abscessus group by 2–3 days compared to control groups. nih.gov In a mouse model of pulmonary M. abscessus disease, this compound at 25 mg/kg once daily produced a reduction in bacterial burden in the lungs of C3HeB/FeJ and BALB/c mice. nih.gov This finding supports the use of this compound as a positive control comparator in preclinical efficacy assessments of agents for the treatment of M. abscessus pulmonary disease in mice. nih.gov

Data Table: this compound in M. abscessus Group Research

Leprosy (as a component of multidrug therapy)

This compound has been a cornerstone of multidrug therapy (MDT) for leprosy for decades. clinicaltrials.eunovartisfoundation.org The World Health Organization (WHO) recommended the use of MDT, including dapsone, rifampicin, and this compound, in 1981 to control primary and secondary resistance to monotherapy, prevent further resistance, and prevent relapses. novartisfoundation.orglshtm.ac.ukmedscape.com

For multibacillary leprosy, the WHO recommends a regimen including rifampicin, this compound, and dapsone. bmj.commedscape.com For paucibacillary leprosy, the WHO initially recommended rifampicin and dapsone, but the Indian Council of Medical Research has recommended adding this compound to the regimen based on published data suggesting it can be safely used along with dapsone and rifampicin for the 6-month MDT. bmj.commedscape.com Adding this compound to paucibacillary leprosy treatment may reduce the repercussions of an incorrect operational classification. nih.gov

A systematic review and meta-analysis evaluating the addition of this compound to paucibacillary leprosy treatment found that cure and relapse rates were not different with the addition of this compound, demonstrating very low certainty of evidence. nih.gov

For rifampicin-resistant leprosy, the WHO recommends treatment with at least two of clarithromycin, minocycline, and a quinolone, in addition to this compound daily for 6 months, followed by this compound and one of the other drugs for an additional 18 months. medscape.com In cases of both rifampicin and ofloxacin resistance, the recommended treatment is clarithromycin, minocycline, and this compound for 6 months, followed by clarithromycin or minocycline and this compound for an additional 18 months. medscape.com

This compound is also used in the treatment of Erythema Nodosum Leprosum (ENL), an inflammatory complication of leprosy. medscape.com

Studies in Animal Models of Mycobacterial Infections

Animal models are crucial for preclinical efficacy evaluations of experimental therapeutics against mycobacterial infections. This compound has been studied in various animal models.

In severe combined immunodeficiency mouse models, treatment with this compound individually significantly reduced bacterial burden in the lung, spleen, and liver in mycobacterial infections. nih.gov The most significant reduction was observed with the combination treatment of this compound and bedaquiline. nih.gov

Studies in mice lacking interferon-gamma demonstrated that this compound treatment afforded a statistically significant reduction in the bacterial burden in the lung, spleen, and liver after 8 days of treatment. nih.gov

A pharmacokinetic-pharmacodynamic (PK-PD) study of this compound in the mouse model suggested that lower doses could be effectively used for the treatment of tuberculosis, although this requires investigation for NTM. nih.govoup.com Achieving adequate exposures quickly seems important, as this compound shows exposure-driven sterilizing and a treatment-shortening effect in TB in mouse models. oup.com

In a murine model of chronic progressive MAC-pulmonary infection, a this compound-containing regimen showed significantly improved treatment efficacy compared to a standard regimen, rapidly reducing bacterial loads and lung inflammation. frontiersin.org

In a mouse footpad model of Mycobacterium ulcerans disease (Buruli ulcer), the combination of rifampin plus this compound was evaluated. plos.org Treatment with this compound alone had little or no impact on lesion size and bacterial load. plos.org However, the combination of RIF+CFZ initially acted more slowly than RIF+streptomycin or RIF+clarithromycin but was as effective as RIF+streptomycin and better than RIF+clarithromycin at preventing relapse of infection in mice treated for 6 weeks and followed up for 24 weeks. plos.org There were no relapses in RIF+streptomycin treated mice, one (5%) relapse in RIF+this compound-treated mice, but >50% in RIF+clarithromycin treated mice. plos.org

In a mouse model of pulmonary M. abscessus disease, this compound at 25 mg/kg once daily produced a reduction in bacterial burden in the lungs. nih.gov This dose and dosing frequency are considered suitable for preclinical efficacy testing of experimental agents against M. abscessus disease in mice. nih.gov

Erythema Nodosum Leprosum (ENL)

Erythema Nodosum Leprosum (ENL) is a serious inflammatory complication of leprosy lshtm.ac.uk. This compound has been recognized for its anti-inflammatory properties in ENL patients since the 1960s rjpbcs.comresearchgate.net. Its effectiveness in suppressing ENL has been supported by numerous studies rjpbcs.comresearchgate.net. Research indicates that this compound treatment can be superior to prednisolone in achieving treatment success and superior to thalidomide in preventing recurrences in ENL patients lshtm.ac.ukresearchgate.net. A Cochrane review of interventions in ENL included randomized controlled trials that showed significant long-term benefits with this compound treatment compared to thalidomide (fewer recurrences) or prednisolone (more treatment success) researchgate.net. One double-blind controlled trial involving 24 lepromatous leprosy patients in reaction demonstrated that this compound controlled ENL symptoms better than prednisolone and appeared significantly superior in preventing recurrence once the reaction was controlled researchgate.net. Another small randomized controlled trial comparing this compound and pentoxifylline in combination with prednisolone for ENL found sustained efficacy in the this compound group researchgate.net.

Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a genetic disorder that affects phagocytes, leading to recurrent infections and granuloma formation. Research has suggested potential applications for this compound in treating CGD patsnap.com. This compound's ability to accumulate in macrophages and its potential interactions with neutrophil granulocytes and macrophages, as well as its influence on phagocytosis, may be relevant in the context of CGD, which involves dysfunctional phagocytes patsnap.commedicaljournals.semedicaljournals.se.

Discoid Lupus Erythematosus

Discoid Lupus Erythematosus (DLE) is a chronic form of cutaneous lupus erythematosus researchgate.netdovepress.com. This compound has been investigated as a treatment option for DLE due to its anti-inflammatory and immunosuppressive properties wikipedia.orgresearchgate.netdovepress.com. Early research suggested it was effective, with one study reporting remission in 17 out of 26 patients with chronic DLE wikipedia.orgresearchgate.net. A randomized clinical trial compared this compound to chloroquine in patients with cutaneous lupus erythematosus, including those with DLE dovepress.com. At 6 months, 82.4% of patients in the this compound group experienced complete or almost complete resolution of skin lesions, compared to 75% in the chloroquine group dovepress.com. While this difference was not statistically significant in this particular study, the findings suggested that this compound could be a therapeutic option for patients with exclusively cutaneous lesions and contraindications to chloroquine dovepress.commedscape.com. Another study administering this compound to nine DLE patients over six months observed complete suppression or improvement in every patient, becoming evident within three months researchgate.netcapes.gov.br.

Here is a summary of findings from a randomized clinical trial comparing this compound and Chloroquine in Cutaneous Lupus Erythematosus (including DLE):

Data derived from Bezerra et al. dovepress.com

Pustular Psoriasis

Pustular psoriasis is a severe form of psoriasis characterized by the eruption of sterile pustules medicaljournalssweden.seoup.com. This compound has been reported to be effective in the treatment of pustular psoriasis wikipedia.orgmedicaljournalssweden.seoup.com. Case reports have described successful treatment outcomes in patients with generalized pustular psoriasis rjpbcs.comwikipedia.org. The mechanism may involve this compound's effect on neutrophil function, which is implicated in the pathogenesis of pustular psoriasis medicaljournalssweden.se. One study found that this compound enhanced the phagocytic function of neutrophil leucocytes in patients with pustulosis palmaris et plantaris, a condition with similarities to pustular psoriasis, and this enhancement was associated with the abatement of pustules medicaljournalssweden.se.

Melkersson-Rosenthal Syndrome

Melkersson-Rosenthal Syndrome (MRS) is a rare neurological disorder characterized by a triad of facial palsy, fissured tongue, and orofacial swelling researchgate.netnih.govpraxis-schuster.ch. Cheilitis granulomatosa, characterized by lip swelling, is often considered a monosymptomatic form of MRS researchgate.netpraxis-schuster.ch. This compound has been demonstrated to be effective in the management of MRS rjpbcs.comwikipedia.orgresearchgate.netnih.gov. Studies have reported complete remission or clinical improvement in patients treated with this compound rjpbcs.com. A pilot study involving seven patients with cheilitis granulomatosa or complete MRS treated with this compound observed beneficial effects in all patients, with prompt and complete suppression of the characteristic variable attacks of lip swelling nih.gov. Persistent residual swelling, however, responded less rapidly and often incompletely nih.gov. Some patients remained symptom-free after drug withdrawal, while others relapsed and responded to a second course of this compound nih.govpraxis-schuster.ch. Histological improvement with clearance of granulomata has been observed in some cases, although edema may persist praxis-schuster.choup.com.

Necrobiosis Lipoidica and Granuloma Annulare

Necrobiosis Lipoidica (NL) and Granuloma Annulare (GA) are chronic granulomatous inflammatory skin disorders medicaljournals.semedicaljournals.senih.govresearchgate.netnih.govresearchgate.net. This compound has been explored as a therapeutic alternative for both conditions rjpbcs.commedicaljournals.semedicaljournals.seresearchgate.netnih.gov. In a study of 20 patients with either disseminated granuloma annulare or NL, 60% responded to this compound treatment, with 30% achieving complete remission medicaljournals.semedicaljournals.seresearchgate.net. A case report described the successful treatment of ulcerated NL with this compound, leading to complete remission within 5 months in a patient resistant to previous therapies rjpbcs.commedicaljournals.semedicaljournals.se. For generalized, severe, and recalcitrant forms of GA, this compound has been among the treatments proposed with variable success mdpi.com. This compound's in vitro antigranulomatous effects and interactions with macrophages and neutrophils may contribute to its activity in these conditions medicaljournals.semedicaljournals.se.

Here is a summary of findings from a study on this compound treatment for Necrobiosis Lipoidica and Granuloma Annulare:

Data derived from Mensing (1989) as reported in Benedix et al. and Hanke et al. medicaljournals.semedicaljournals.seresearchgate.netnih.gov

Rheumatoid Arthritis and Type 1 Diabetes (Potential Applications)

Research suggests this compound may have potential applications in treating rheumatoid arthritis (RA) and type 1 diabetes (T1D). Studies have indicated that this compound acts as a Kv1.3 (KCNA3) channel blocker in human T cells. wikipedia.org This is notable because Kv1.3-high effector memory T cells (TEM) are implicated in the development of these autoimmune diseases, and Kv1.3 activity is crucial for TEM stimulation and proliferation by regulating calcium influx. wikipedia.org While this compound's immunosuppressive effects were observed in animal models, inhibiting macrophage and neutrophil motility and lymphocyte proliferation in vitro, evidence supporting its use in conditions other than leprosy is currently considered insufficient. wikipedia.org

Triple-Negative Breast Cancer

Preclinical studies have shown this compound's effectiveness against triple-negative breast cancer (TNBC), an aggressive subtype lacking targeted therapy. nih.govunige.chcureswithinreach.orgbreastcancer-news.com Research indicates that this compound inhibits Wnt signaling and cell proliferation in TNBC cell lines and suppresses tumor growth in mouse xenograft models. nih.govunige.chunil.chbreastcancer-news.com this compound has also demonstrated compatibility with doxorubicin, showing additive effects on tumor growth suppression without synergistic adverse effects in mouse models. nih.govunil.ch This, along with its established pharmacokinetic profile, positions this compound as a candidate for repositioning clinical trials in TNBC. nih.govunil.ch

Colorectal, Liver, Ovarian, and Brain Tumors

Beyond TNBC, the applicability of this compound is being explored in other Wnt-dependent cancers, including hepatocellular carcinoma (liver), glioblastoma (brain), colorectal, and ovarian cancers. nih.govunige.ch Studies using panels of cell lines from these cancer types suggest that this compound's efficacy correlates with the basal levels of Wnt pathway activation and its ability to inhibit Wnt signaling. nih.gov this compound has shown antiproliferative effects in colorectal cancer cell lines, with varying IC50 values depending on the cell line. nih.gov Research indicates that this compound decreases cell growth in some colorectal, liver, ovarian, and brain tumor cell lines, with more pronounced decreases observed in cell lines exhibiting stronger Wnt signaling overactivation. unige.ch In glioblastoma, this compound has been shown to suppress cell proliferation, induce apoptosis, and inhibit invasion in vitro by downregulating Wnt6-mediated Wnt/β-catenin pathway activation. nih.gov

Here is a table summarizing some preclinical findings on this compound's effects on various cancer cell lines:

Multiple Myeloma

This compound has shown promise in the treatment of multiple myeloma (MM). Studies have identified this compound as a potent aryl hydrocarbon receptor (AHR) antagonist and a suppressor of polyamine biosynthesis, both of which are relevant in MM. nih.govwakehealth.edu In a transgenic mouse model of MM and in immunocompromised mice with MM cell xenografts, this compound demonstrated high efficacy, comparable to bortezomib, a standard MM treatment. nih.govwakehealth.edu In vitro studies on the U266 MM cell line showed significant growth suppression with this compound treatment, achieving an IC50 value of 9.8 ± 0.7 μM. researchgate.net this compound also exhibited a synergistic inhibitory effect when combined with cisplatin in this cell line. researchgate.net Mechanistic studies suggest this compound induces apoptosis through mitochondrial membrane depolarization, changes in cell membrane asymmetry, and increased caspase-3 activity in MM cells. researchgate.net Furthermore, this compound has been shown to synergize with proteasome inhibitors (like ixazomib) and immunomodulatory drugs (like lenalidomide) in various MM cell lines, including those resistant to standard treatments. researchgate.net

Synergistic Effects with Immunotherapy (e.g., Anti-PD-1/CTLA-4)

Recent research highlights this compound's potential to enhance the efficacy of dual immune checkpoint blockade (ICB) therapy, specifically with anti-PD-1 and CTLA-4 inhibitors. houstonmethodist.orgsafetherapeutics.comresearchgate.netwilliamscancerinstitute.comnih.govaacrjournals.org A screening of FDA-approved drugs identified this compound as a compound that could optimize anti-PD-1 + CTLA-4 ICB. researchgate.netnih.gov Studies in various mouse models of cancer, including colorectal cancer, melanoma, B-cell lymphoma, and lung carcinoma, demonstrated that this compound synergizes with ICB in reducing tumor burden, leading to complete eradication of advanced tumors in some cases when used in combination. williamscancerinstitute.comaacrjournals.org this compound treatment also restored responsiveness in several models resistant to ICB. aacrjournals.org Mechanistically, this compound promotes E2F1 activation in CD8+ T cells, which helps overcome resistance and enhances antitumor immune responses. safetherapeutics.comresearchgate.netnih.gov It also counteracts pathogenic Th17 cells, which are associated with immune-related adverse events (irAEs), potentially mitigating these side effects without compromising antitumor efficacy, unlike steroids. safetherapeutics.comresearchgate.netwilliamscancerinstitute.comnih.govaacrjournals.org In glioblastoma mouse models, the combination of this compound and anti-PD-1 therapy significantly reduced tumor growth and intracranial invasion, prolonging survival and reshaping the tumor immune microenvironment by increasing cytotoxic CD8+ T cell infiltration and reducing regulatory T cells. nih.gov

Cryptosporidiosis

Research has identified this compound as a potential treatment for cryptosporidiosis, a diarrheal disease caused by Cryptosporidium species. A high-throughput screen of a large compound library identified this compound among hits with sub-micromolar activity against C. parvum and C. hominis. plos.org In vitro studies demonstrated potent and selective activity against C. parvum, with an EC₅₀ of 15 nM. plos.org

This compound is known to accumulate in epithelial cells of the small intestine, the primary site of Cryptosporidium infection, which supports its potential as a treatment. plos.org In a mouse model of acute cryptosporidiosis, daily administration for three consecutive days or a single high dose resulted in a reduction of oocyst shedding. plos.org

Despite promising preclinical results, a phase 2a clinical trial evaluating this compound in HIV-infected adults with cryptosporidiosis did not show improved microbiological or clinical outcomes compared to placebo. asm.orgasm.orgnih.gov Analysis suggested that the this compound concentrations achieved in the trial participants were likely below the levels required for efficacy against cryptosporidiosis, despite using a dosing regimen exceeding typical recommendations for mycobacterial therapy. asm.orgasm.org

Table 1: Summary of this compound Research in Cryptosporidiosis

COVID-19

This compound has been investigated for its potential activity against SARS-CoV-2, the virus responsible for COVID-19. Studies have shown that this compound possesses pan-coronaviral inhibitory activity and can antagonize SARS-CoV-2 replication in various in vitro systems, including human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. nih.govresearchgate.net

The compound appears to inhibit multiple steps of viral replication, suggesting diverse underlying antiviral mechanisms. nih.govresearchgate.net Research indicates that this compound can block viral entry into cells and disrupt RNA replication. news-medical.netcontagionlive.com In a hamster model of SARS-CoV-2 pathogenesis, both prophylactic and therapeutic administration of this compound significantly reduced viral load in the lung and decreased fecal viral shedding. nih.govresearchgate.netnews-medical.netcontagionlive.comabs-cbn.com It also prevented the exaggerated inflammatory response, or "cytokine storm," associated with severe COVID-19. news-medical.netcontagionlive.comabs-cbn.comscitechdaily.com

Furthermore, this compound has shown synergistic effects when administered with remdesivir in hamster models, improving viral control and potentially allowing for reduced dosages of both drugs. news-medical.netabs-cbn.comscitechdaily.comoup.com

Table 2: Summary of this compound Research in COVID-19

Other Protozoal and Fungal Infections (e.g., Trypanosoma cruzi, Babesia, Candida albicans)

This compound has demonstrated activity against a range of protozoal and fungal pathogens. It is reported to be susceptible against parasites including Trypanosoma cruzi and Babesia species. oup.comresearchgate.netoup.com Research indicates that this compound can inhibit trypanosomal proline transporters and enhance the retention of benznidazole, a common treatment for Trypanosoma cruzi infections. nih.govfrontiersin.orgplos.org

Studies have also shown this compound's activity against the yeast Candida albicans. oup.comresearchgate.netoup.com this compound can potentiate the effects of several antifungal drugs, including fluconazole, posaconazole, and caspofungin, against Candida species and Aspergillus fumigatus. nih.govplos.orgresearchgate.net It is suggested that this compound elicits cell membrane stress and activates protein kinase C-like 1 (Pkc1) signaling, which is also targeted by some antifungal agents like fluconazole and caspofungin in Candida albicans. nih.govplos.org In vitro studies have shown that the addition of this compound can reduce the minimum inhibitory concentrations (MICs) of caspofungin for various Candida species, including some clinical isolates of C. albicans. researchgate.net

Table 3: this compound Activity Against Other Protozoa and Fungi

Huntington's Disease and Other PolyQ Protein-Related Diseases

Research has explored the potential of this compound in the context of neurodegenerative diseases, particularly those linked to polyglutamine (polyQ) protein expansions, such as Huntington's disease (HD). These diseases are characterized by the aggregation of proteins containing expanded CAG repeats. ki.sescilifelab.seresearchgate.netbiorxiv.orgnih.govresearchgate.net

A high-throughput chemical screen aimed at identifying compounds that reduce the toxicity of a protein fragment from Huntington's disease protein (huntingtin) containing an expanded polyQ tract (Htt-Q94) identified this compound as a hit. researchgate.netbiorxiv.orgnih.govresearchgate.net Subsequent validation in several in vitro models confirmed this finding. researchgate.netbiorxiv.orgnih.govresearchgate.net

Computational analyses and biochemical assays suggest that this compound acts as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ). researchgate.netbiorxiv.orgnih.govresearchgate.netki.se PPARγ has been previously implicated as a potential therapeutic target in HD due to its role in stimulating mitochondrial biogenesis. researchgate.netbiorxiv.orgnih.gov In line with this mechanism, this compound was found to rescue mitochondrial dysfunction triggered by Htt-Q94 expression. researchgate.netbiorxiv.orgnih.govresearchgate.netki.se Importantly, this compound also demonstrated the ability to limit polyQ toxicity in in vivo models, including developing zebrafish and neuron-specific worm models of polyQ disease. researchgate.netbiorxiv.orgnih.gov While these preclinical findings are promising, it is noted that this compound's efficiency in entering the nervous system may be a limitation requiring further investigation in mammalian models. ki.sescilifelab.se

Table 4: this compound Research in Huntington's Disease and PolyQ Diseases