Cimetidine

Competitive Inhibition Dynamics at Gastric Parietal Cells

The primary mechanism by which this compound reduces gastric acid secretion is through competitive inhibition of histamine at the histamine H2 receptors located on the basolateral membrane of gastric parietal cells. drugbank.compatsnap.comnih.govpediatriconcall.commedicaldialogues.indroracle.ai Parietal cells are the cells responsible for producing and secreting hydrochloric acid in the stomach. patsnap.com Histamine, released from enterochromaffin-like (ECL) cells in the stomach, stimulates these H2 receptors, initiating a signaling cascade that leads to acid production. patsnap.com By competitively binding to these receptors, this compound blocks histamine's ability to bind and activate them. drugbank.compatsnap.comnih.govpediatriconcall.commedicaldialogues.indroracle.ai This competitive blockade reduces both basal and stimulated gastric acid secretion, as well as gastric volume and acidity. drugbank.commedicaldialogues.indroracle.ai Stimuli whose effects on acid secretion are inhibited by this compound include food, histamine, pentagastrin, caffeine, and insulin. droracle.ai

Molecular Interactions with H2 Receptors

At the molecular level, this compound's interaction with the histamine H2 receptor involves binding to specific sites on the receptor protein. This compound has been found to bind to the H2 receptor with a dissociation constant (Kd) of 42 nM. wikipedia.org Studies investigating the molecular basis of histamine interaction with the H2 receptor have identified key amino acid residues involved in ligand binding. For instance, Asp98 in the third transmembrane domain of the receptor is considered essential for histamine binding and action, likely interacting with the cationic amine moiety of histamine. nih.gov Asp186 is suggested to define H2 selectivity, while Thr190 is important for establishing the kinetics of histamine binding. nih.gov While these studies primarily focus on histamine binding, they provide context for the types of molecular interactions that antagonists like this compound would engage in at the same receptor site. Computational studies have also explored the importance of hydrogen bonding interactions for the binding of histaminergic ligands, including this compound, to the H2 receptor, suggesting the involvement of residues like Asp98, Asp186, Tyr250, Lys175, and Thr190 in the binding site. mdpi.com

Isoenzyme Specificity and Inhibition Profiles (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4)

This compound is recognized as a potent inhibitor of several CYP isoenzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. wikipedia.orgdrugbank.comnih.gov Research indicates that this compound appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, being described as a moderate inhibitor of these isoforms. wikipedia.org These six isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) are responsible for the metabolism of a large proportion of commonly used drugs. wikipedia.orgnih.govpharmajournal.net

Studies have investigated the inhibitory effects of this compound on specific CYP isoforms in human liver microsomes. For CYP1A2, this compound shows significantly greater inhibition compared to other H2-receptor antagonists like ranitidine and ebrotidine. nih.gov Similarly, this compound exhibits much stronger inhibition of CYP2D6 activity than ranitidine or ebrotidine. nih.gov For CYP3A4/5, ebrotidine appears to be a stronger inhibitor than this compound, which is in turn a much stronger inhibitor than ranitidine. nih.gov

An interactive data table summarizing the relative inhibitory effects of this compound on key CYP isoforms based on research findings could be presented as follows:

Note: In an interactive table, clicking on a CYP isoenzyme could potentially link to more detailed data or research findings related to this compound's inhibition of that specific enzyme.

Competitive and Mechanism-Based (Suicide) Inhibition Mechanisms

This compound is reported to be a competitive and reversible inhibitor of several CYP enzymes. wikipedia.org Competitive inhibition occurs when the inhibitor molecule competes with the substrate molecule for binding to the enzyme's active site. mdpi.com this compound can reversibly inhibit CYP enzymes by binding directly to the complexed heme-iron in the active site, often via one of its imidazole ring nitrogen atoms, thereby blocking the oxidation of other substrates. wikipedia.org

In addition to reversible competitive inhibition, mechanism-based inhibition, also known as suicide inhibition, has been identified for this compound's inhibition of certain CYP isoforms, particularly CYP2D6. wikipedia.orgubc.caresearchgate.netmdpi.comdrugbank.comdvm360.com Mechanism-based inhibition involves the metabolic activation of the inhibitor by the enzyme itself to a reactive intermediate that then binds irreversibly or quasi-irreversibly to the enzyme, leading to long-lasting inactivation. mdpi.comdrugbank.comdvm360.com This process requires catalytic activity of the enzyme to generate the inhibitory species. mdpi.comdvm360.com Studies have suggested that this compound acts as a mechanism-based inactivator of CYP2D6. ubc.caresearchgate.net

Formation of Metabolite-Intermediate Complexes with Cytochrome P450

A key aspect of the mechanism-based inhibition by this compound involves the formation of a metabolite-intermediate (MI) complex with the cytochrome P450 enzyme. ubc.camdpi.comnih.govnih.gov This occurs when a metabolite of this compound, formed during the catalytic cycle of the CYP enzyme, binds tightly and stably to the heme iron of the enzyme. mdpi.comnih.govnih.gov This complex renders the enzyme inactive. mdpi.com

Evidence for the formation of a this compound metabolite-intermediate complex has been provided by studies, particularly in rats, where it was shown to selectively inhibit CYP2C11 by forming such a complex. nih.govnih.gov This complex formation can be generated in vitro by incubating microsomes with this compound in the presence of NADPH, a necessary cofactor for CYP activity. nih.gov The spectral properties observed in these studies are consistent with the presence of an MI complex. nih.gov While initially studied in animal models, the concept of metabolite-intermediate complex formation contributes to the understanding of this compound's inhibitory effects on human CYPs as well, particularly in the context of mechanism-based inhibition observed for enzymes like CYP2D6. ubc.ca The formation of these stable complexes leads to a time-dependent loss of enzyme activity that is not easily reversed, requiring the synthesis of new enzyme for activity recovery. dvm360.com

This compound Sulfoxide Formation and Other Metabolites

The primary metabolite of this compound is this compound sulfoxide, formed by the oxidation of the side-chain sulfur drugbank.comiarc.fr. This compound sulfoxide accounts for an estimated 10-15% of total elimination drugbank.com. Some sources indicate that this compound sulfoxide represents approximately 30% of the excreted material in humans wikipedia.org. Research has also identified a minor metabolite resulting from hydroxylation of a methyl group on the imidazole ring, contributing about 4% to total elimination drugbank.com. Other identified metabolites include this compound sulfone and 5-hydroxythis compound, and 5-hydroxythis compound sulfoxide ontosight.ai. Studies using small intestinal microsomes from different species have investigated the S-oxidation of this compound, suggesting contributions from both flavin-containing monooxygenases and cytochrome P450 enzymes in this process nih.gov.

Here is a summary of identified this compound metabolites:

Renal Secretion Inhibition of Co-administered Drugs

This compound is known to interact with numerous other medications, partly due to its ability to inhibit renal tubular secretion of organic cations nih.govcapes.gov.br. This occurs through competition for specific transport systems, particularly the organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) in the renal tubules capes.gov.brnih.gov. Studies have shown that this compound can inhibit the renal clearance of various cationic drugs by interfering with these transporters nih.govresearchgate.netnih.govmdpi.com.

Research using in vitro models and in vivo studies has investigated the interaction of this compound with transporters like OCT2 and MATE1/2-K nih.govmdpi.comresearchgate.net. This compound has been identified as an inhibitor of OCT2 and MATEs, with some studies suggesting a greater potency for MATE1 nih.govmdpi.com. The inhibition of OCT2 by this compound may be substrate-dependent, meaning the extent of inhibition can vary depending on the co-administered drug researchgate.net. For example, studies have shown that this compound can significantly inhibit the renal secretion of drugs like metformin and glycopyrronium, which are substrates for these transporters researchgate.netnih.govbiorxiv.org. This inhibition can lead to increased plasma concentrations and altered pharmacokinetics of the co-administered drugs nih.govnih.govbiorxiv.org.

Studies have utilized this compound as a probe inhibitor to investigate the role of organic cation transporters in the disposition of other drugs researchgate.netnih.gov. Research involving co-administration of this compound with drugs like amiloride and glycopyrronium has demonstrated reductions in their renal clearance and increased systemic exposure nih.govnih.gov. For instance, this compound reduced the renal clearance of amiloride by a mean of 17% in healthy subjects nih.gov. Similarly, co-administration with this compound resulted in a 22% increase in the total systemic exposure (AUC) of glycopyrronium, correlated with a slight decrease in its renal clearance nih.gov. These findings underscore the importance of considering potential renal secretory interactions when this compound is co-administered with other renally cleared cationic compounds.

Natural Killer (NK) Cell Activity Enhancement

Natural Killer (NK) cells are crucial for recognizing and eliminating abnormal cells, such as tumor cells and virus-infected cells. Research indicates that this compound can enhance NK cell activity. researchgate.netnih.govmdpi.com Studies have shown that this compound augmented natural killer cell activity in both healthy individuals and patients with certain cancers, such as melanoma and colorectal carcinoma. nih.gov This enhancement was observed in vitro and, in some cases, in vivo. nih.gov One study noted that this compound tended to enhance NK cell activity in splenic lymphocytes of rats. spandidos-publications.com Another study on patients with chronic lymphocytic leukemia (B-CLL) showed that this compound treatment increased peripheral blood NK activity. nih.gov

Here is a table summarizing some findings on this compound's effect on NK cells:

Dendritic Cell (DC) Antigen-Presenting Activity

Dendritic cells (DCs) are critical antigen-presenting cells that bridge the innate and adaptive immune responses by processing antigens and presenting them to T lymphocytes. virtualtrials.orgresearchgate.net this compound has been shown to influence DC function, specifically enhancing their antigen-presenting capacity. researchgate.netnih.govmdpi.comvirtualtrials.org Studies have demonstrated that this compound can stimulate the maturity of immature DCs and enhance their ability to prime T cells. researchgate.net In patients with colorectal cancer, this compound modulated the antigen-presenting capacity of dendritic cells. virtualtrials.orgnih.gov This effect may contribute to an enhanced anti-tumor cell-mediated immune response. nih.gov While some research suggests this effect might be mediated by a mechanism not directly related to H2 receptors, other studies highlight the role of H2R antagonism in reversing histamine's inhibitory effects on DC function. nih.govresearchgate.net

Neutrophil, Monocyte, and Macrophage Function Modulation

Neutrophils, monocytes, and macrophages are key phagocytic cells involved in innate immunity and inflammation. researchgate.netnih.govuni.lu this compound has been reported to have stimulatory effects on the effector functions of these cells. researchgate.netnih.govuni.lu Histamine, through H2R, can modulate the function of these cells. researchgate.netnih.govuni.lu this compound, by blocking H2R, can reverse some of these effects. researchgate.netnih.govuni.lu For instance, histamine can inhibit human neutrophil chemotaxis via H2R, an effect that this compound may counteract. uni.lu this compound has also been shown to induce the production of interleukin (IL)-18, an antitumor cytokine, by human monocytes and dendritic cells. This effect was observed with this compound but not with other H2R antagonists like ranitidine and famotidine, suggesting a potential H2-agonist activity of this compound in this context. In some studies, this compound has been shown to influence macrophage polarization, potentially favoring anti-tumor M1 macrophages. mdpi.comnih.gov

T-Lymphocyte Subpopulation Modulation (CD3+, CD4+, CD8+ T Cells)

T lymphocytes, including CD3+, CD4+ (helper T cells), and CD8+ (cytotoxic T cells), play central roles in cell-mediated immunity. researchgate.netnih.govuni.luwaocp.org Research indicates that this compound can modulate these T cell subpopulations. researchgate.netnih.govuni.lumdpi.comresearchgate.net Histamine can suppress CD8+ cytotoxic T cells via H2R, and this compound has been shown to reverse this suppression, potentially enhancing antitumor activity. researchgate.net this compound has been reported to increase the total number of CD3+, CD4+, and CD8+ T cells in some contexts. researchgate.netnih.govmdpi.com For example, a study in a colon cancer model showed that this compound increased the CD3+, CD4+, and CD8+ T cell populations in the tumor microenvironment. mdpi.com However, another study in HIV-infected patients found no significant differences in CD4+ cell counts between this compound and placebo groups. jwatch.orgoup.com

This compound's effects on T cell subsets can vary depending on the context. It has been suggested to activate Th1 cells, which are involved in cell-mediated immunity, and potentially lower Th2 cell activity, which is associated with humoral immunity and allergic responses. clinicaltrials.eu this compound may also reduce the activity of regulatory T cells (Tregs), which suppress immune responses. researchgate.netresearchgate.net

Here is a table summarizing some findings on this compound's effect on T cell subpopulations:

Regulatory T Cell (Treg) Function Inhibition

Research indicates that this compound can exert inhibitory effects on the function of regulatory T cells (Tregs). Tregs play a crucial role in maintaining immune tolerance and suppressing immune responses. Studies have shown that this compound can impair Treg cell activity. waocp.orgtandfonline.comresearchgate.net This inhibition of Treg function by this compound may contribute to enhanced immune responses. tandfonline.comresearchgate.net For instance, this compound has been reported to enhance immune responses to hepatitis B DNA vaccination, potentially via the inhibition of Treg cells. tandfonline.comresearchgate.net Furthermore, this compound has been shown to lead to the degradation of FOXP3, a key transcription factor associated with Treg cells, which is accompanied by impaired Treg cell activity. waocp.orgresearchgate.net

Th1, Th2, and Th17 Cytokine Profile Alterations

This compound has been observed to modulate the balance of T helper (Th) cell subsets, specifically altering the Th1, Th2, and Th17 cytokine profiles. Th1 cells are generally associated with cell-mediated immunity, Th2 cells with humoral immunity and allergic responses, and Th17 cells with inflammation and defense against extracellular pathogens. tandfonline.comtandfonline.com

Studies have suggested that this compound can influence both Th1- and Th2-type immune responses. tandfonline.com Some research indicates that this compound can enhance Th1-type cytokines while reducing Th2-associated cytokines. researchgate.net For example, in the context of Lyme disease, where suppression of Th1 responses may occur, this compound therapy has been shown to promote levels of Th1-associated cytokines such as IL-12, TNF-α, and IFN-γ, while reducing levels of the Th2-associated cytokine IL-10, potentially helping to restore immune balance. researchgate.net

Furthermore, this compound has been reported to potentiate Th1/Th2 dual polarization. tandfonline.com In addition to its effects on Th1 and Th2 responses, this compound has also been shown to influence Th17 cells. Studies have indicated that this compound can lead to the upregulation of Th1 and Th17 cells while downregulating Th2 and Treg cells. researchgate.netresearchgate.net

Tumor-Infiltrating Lymphocyte (TIL) Response Augmentation

This compound has demonstrated the ability to augment the response of tumor-infiltrating lymphocytes (TILs). TILs are immune cells that migrate into tumors and are crucial for the anti-tumor immune response. Enhancing TIL activity is a key strategy in cancer immunotherapy.

Research suggests that this compound can enhance the tumor-infiltrating lymphocyte response. mdpi.com Perioperative administration of this compound has been shown to improve systematic immune response and tumor-infiltrating lymphocytes in patients with colorectal cancer. waocp.orgcancerchoices.org Clinical studies have revealed higher rates of tumor-infiltrating lymphocyte responses after surgery among patients with gastrointestinal cancer treated with this compound compared to control groups. cancerchoices.org Similarly, enhanced lymphocyte responses have been observed after elective resection in patients with colorectal carcinoma treated with this compound. cancerchoices.orgnih.gov this compound has also been shown to increase the number of TILs in colorectal and gastric cancer patients. nih.gov

Interleukin (IL) Regulation (e.g., IL-2, IL-10, IL-12, IL-17)

This compound has been shown to regulate the expression of several interleukins. Studies in animal models have demonstrated that this compound can significantly augment the levels of IL-2, IL-10, IL-12, and IL-17, particularly in contexts of immunosuppression such as after burn injury. tandfonline.comresearchgate.nettandfonline.comnih.gov

Specifically:

IL-2: this compound has been shown to significantly augment IL-2 levels. tandfonline.comresearchgate.nettandfonline.comnih.gov IL-2 is a key cytokine involved in T cell proliferation and differentiation. tandfonline.comtandfonline.comwikipedia.org

IL-10: this compound treatment has been observed to enhance IL-10 levels in certain conditions. tandfonline.comresearchgate.nettandfonline.comnih.gov IL-10 is generally considered an anti-inflammatory cytokine that can suppress immune responses. tandfonline.comtandfonline.comnih.gov

IL-12: this compound can significantly increase IL-12 levels. tandfonline.comresearchgate.nettandfonline.comnih.gov IL-12 is a crucial cytokine for promoting Th1 cell differentiation and cell-mediated immunity. waocp.orgtandfonline.comtandfonline.com

IL-17: Augmentation of IL-17 levels by this compound has also been reported. tandfonline.comresearchgate.nettandfonline.comnih.gov IL-17 is a cytokine produced by Th17 cells and is involved in inflammatory responses and host defense. tandfonline.comtandfonline.com

In addition to these, this compound has been reported to increase the levels of other cytokines such as IFN-γ, TNF-α, and IL-15. mdpi.comwaocp.orgresearchgate.netnih.gov Conversely, this compound can inhibit histamine-induced IL-10 expression while promoting histamine-reduced IL-12 secretion in dendritic cells. waocp.org

Transforming Growth Factor-Beta (TGF-β) Modulation

This compound has been shown to modulate the levels of Transforming Growth Factor-Beta (TGF-β). tandfonline.comresearchgate.nettandfonline.com TGF-β is a pleiotropic cytokine with various functions, including immune regulation and tissue fibrosis. tandfonline.comtandfonline.comnih.govnih.govresearchgate.net It is also considered a Treg cytokine. tandfonline.comresearchgate.net

Research indicates that this compound can significantly diminish elevated TGF-β levels in certain pathological contexts, such as after burn injury. tandfonline.comresearchgate.nettandfonline.comnih.gov This reduction in TGF-β by this compound may contribute to its immune-enhancing effects, as TGF-β can suppress immune responses. tandfonline.comresearchgate.nettandfonline.com

Immune Modulation in Post-Burn Injury Contexts

Research indicates that this compound can significantly augment immune responses that are typically suppressed following thermal trauma. Studies in animal models have demonstrated that this compound restores burn-induced suppression of delayed-type hypersensitivity (DTH) responses. tandfonline.comtandfonline.comresearchgate.net DTH response, a measure of cell-mediated immunity, is markedly suppressed for up to 30 days after burn trauma, with maximal suppression occurring between 10 to 14 days post-injury. researchgate.netresearchgate.net Administration of this compound has been shown to significantly enhance DTH responses at various time points post-burn. tandfonline.comtandfonline.comresearchgate.net

Beyond DTH responses, this compound has been observed to influence cytokine levels in the post-burn period. Studies have shown that this compound can significantly augment the levels of several interleukins, including IL-2, IL-10, IL-12, and IL-17, which are normally suppressed after thermal trauma. tandfonline.comtandfonline.comresearchgate.net For instance, significant increases in IL-2, IL-10, IL-12, and IL-17 levels were observed at specific post-burn day (PBD) time points in this compound-treated burned subjects compared to untreated burned counterparts. tandfonline.comtandfonline.comresearchgate.net Conversely, this compound significantly diminished burn-induced elevated levels of TGFβ, a regulatory T (Treg) cell cytokine, at later time points. tandfonline.comtandfonline.com This effect is consistent with the understanding that this compound enhances immune responses, in part, by down-regulating Treg cell function. tandfonline.comtandfonline.com

Furthermore, this compound has been shown to improve T-cell proliferation and enhance the percentage of CD8+ T cells in burn-injured patients. researchgate.net While the percentage of CD3+ and CD4+ T cells and B cells (CD19+ HLA-DR+ cells) did not change significantly in this compound-treated patients compared to untreated individuals, the restoration of peripheral blood mononuclear cell (PBMC) proliferation rate was observed following this compound treatment. nih.gov

The beneficial impacts of this compound on immune parameters have also been noted in the context of spleen architecture in animals with burn injuries. waocp.org

Here is a summary of the effects of this compound on immune parameters in post-burn injury contexts based on research findings:

Effects on Hypersensitivity Responses

This compound's influence on hypersensitivity responses has also been explored in research. Studies have linked the use of this compound to an increase in Th1-type cytokine-mediated immune responses and delayed-type hypersensitivity reactions. springermedizin.de In a study involving mice sensitized with ovalbumin, administration of this compound resulted in a significant increase in both specific-IgE and IL-5 levels in the culture supernatants of spleen cells. springermedizin.de However, levels of Th1-, Th2-, and Th17-type cytokines did not differ between treated and untreated mice in this specific study. springermedizin.de

Further research in humans has demonstrated that this compound can exhibit pro-inflammatory effects, including increased release of Th1-type cytokines, particularly IL-12 and IL-2. springermedizin.de

This compound has been shown to reduce the suppressor activity of Foxp3+ CD4+ CD25+ Treg cells, potentially through increased degradation of Foxp3. springermedizin.de This reduction in Treg cell activity could contribute to enhanced immune responses, including those involved in delayed hypersensitivity. springermedizin.de

In a study on allergic contact hypersensitivity (ACH) in mice, treatment with this compound during the induction phase significantly enhanced the ear swelling response throughout the first 48 hours after challenge. nih.gov Histological examination revealed a more intense cellular infiltrate in this compound-treated animals. nih.gov This enhancement of ACH by this compound is thought to be independent of effects on mast cells or antigen-presenting cells, but may be related to an inhibition of the induction of T-suppressor cells at the time of sensitization. nih.gov

While some research suggests a link between this compound and enhanced hypersensitivity responses, it's important to note that the role of H2-antagonists in the treatment of conditions like urticaria is considered weak and unreliable by some reviews. springermedizin.de However, the addition of an H2-antagonist to H1-antagonist therapy has shown promise in specific types of urticaria, such as cholinergic urticaria, which involves complex pathogenesis beyond solely IgE-mediated mechanisms. springermedizin.de

Here is a summary of the effects of this compound on hypersensitivity responses based on research findings:

Colorectal Carcinoma: Adjuvant Therapy and Survival Benefit Studies

Numerous studies have investigated this compound as an adjuvant therapy in colorectal carcinoma patients following surgical resection. nih.govloveyourbuns.orgijsra.net The rationale behind this research stems from early observations suggesting a potential survival benefit associated with this compound use in cancer patients. nih.govloveyourbuns.org

Another study involving 64 colorectal cancer patients who underwent curative operations examined the effects of this compound treatment on survival and recurrence. researchgate.net Patients in the this compound group received this compound along with 5-fluorouracil, while the control group received 5-fluorouracil alone. researchgate.net The 10-year survival rate in the this compound group was significantly higher compared to the control group. researchgate.net

Table 1: 10-Year Survival Rates in a Colorectal Cancer Study (this compound + 5-FU vs. 5-FU alone) researchgate.net

Note: Data derived from a study of 64 colorectal cancer patients who received curative operation. researchgate.net

Perioperative this compound Administration Research

The timing of this compound administration relative to surgery has been a focus of research, particularly in the perioperative period. ecancer.orgnih.govnih.gov Surgical resection, a common cancer treatment, can lead to post-surgical immune suppression, potentially increasing the risk of recurrence or metastatic spread. ecancer.org Perioperative this compound administration has been investigated for its potential to mitigate this immunosuppression and reduce the risk of disease recurrence in colorectal cancer patients undergoing curative resection. ecancer.orgnih.govresearchgate.net

An Australian and New Zealand Phase II trial is currently investigating the perioperative use of this compound in patients with colorectal cancer treated with curative resection. ecancer.org The primary outcome of this study is 2-year disease-free survival, with subgroup analysis focusing on patients with positive tumor staining for sialyl Lewis antigens. ecancer.org

A retrospective study involving stage III colorectal cancer patients who underwent surgical resection and received chemotherapy investigated the effect of perioperative this compound. ijsra.netnih.gov Ten out of 38 patients received perioperative this compound in addition to chemotherapy. ijsra.netnih.gov The results indicated that time to recurrence and cancer deaths were prolonged in the chemotherapy plus this compound group compared to the group receiving chemotherapy alone. nih.gov

Table 2: Time to Recurrence in Stage III Colorectal Cancer Patients (Chemotherapy + this compound vs. Chemotherapy alone) nih.gov

Note: Data derived from a retrospective study of 38 stage III colorectal cancer patients. nih.gov

Inhibition of Cancer Cell Adhesion and Metastasis (e.g., E-selectin)

One proposed mechanism for this compound's antineoplastic effect is its ability to inhibit cancer cell adhesion to endothelial cells, thereby potentially preventing metastasis. ecancer.orgaacrjournals.orgchemicalbook.com This effect is believed to be mediated, in part, by the interaction between tumor sialyl Lewis antigens and E-selectin expressed on the endothelium. ecancer.orgaacrjournals.orgchemicalbook.com

Studies have demonstrated that this compound can block the adhesion of colorectal tumor cell lines to endothelial cell monolayers in vitro and suppress the metastasis of tumor cells in nude mouse models. aacrjournals.org This anti-adhesive effect appears to involve the down-regulation of E-selectin expression on endothelial cells. aacrjournals.orgniph.go.jp Notably, this effect seems to be independent of this compound's histamine H2 receptor antagonist activity, as other H2 receptor antagonists like famotidine and ranitidine have not shown similar effects on cell adhesion or patient survival. aacrjournals.org this compound has been shown to inhibit the increase in E-selectin expression at the protein level without affecting mRNA expression. chemicalbook.com

Correlation with Sialyl Lewis-X/A Expression

Research suggests a correlation between the effectiveness of this compound treatment in colorectal cancer patients and the expression levels of sialyl Lewis-X (sLeX) and sialyl Lewis-A (sLeA) antigens on tumor cells. ecancer.orgchemicalbook.comnih.govnih.gov These antigens are ligands for E-selectin and their expression on tumor cells is associated with poor prognosis and metastasis. chemicalbook.comnih.govnih.govnih.gov

Studies have shown that this compound treatment significantly improved survival in colorectal cancer patients whose tumors expressed high levels of sLeX and sLeA. nih.govnih.gov Conversely, in patients with no or low levels of sLeX and sLeA expression, this compound did not show a significant beneficial effect on survival. nih.govnih.gov

Table 3: 10-Year Cumulative Survival Rates in Colorectal Cancer Patients Stratified by Sialyl Lewis-X Expression nih.govnih.gov

Note: Data derived from a study of colorectal cancer patients. nih.govnih.gov

Similarly, studies stratifying patients based on sLeA expression have shown a beneficial effect of this compound in patients with high sLeA levels. nih.gov

Table 4: 10-Year Cumulative Survival Rates in Colorectal Cancer Patients Stratified by Sialyl Lewis-A Expression nih.gov

Note: Data derived from a study of colorectal cancer patients. nih.gov

These findings suggest that the expression of sialyl Lewis antigens on tumor cells may serve as a predictive marker for the efficacy of this compound as an adjuvant therapy in colorectal cancer. nih.govnih.gov

Gastric Cancer Research

This compound has also been investigated in the context of gastric cancer. Early studies explored the potential effect of this compound on survival after gastric cancer treatment. ecancer.org While some initial reports suggested a potential benefit, larger, more recent studies have yielded varied and sometimes inconclusive results regarding this compound's impact on survival in gastric cancer patients. nih.gov However, the inhibitory effect of this compound on cell adhesion has also been demonstrated for gastric cancer cells. ecancer.orgresearchgate.net

Melanoma and Renal Cell Carcinoma Investigations

Investigations into this compound's effects have extended to melanoma and renal cell carcinoma. aacrjournals.orgnih.govmdpi.comoncology-central.comresearchgate.net Early clinical evidence suggested that this compound might have some effect on renal cell carcinoma. ecancer.orgcancerchoices.org A small trial combining this compound with coumarin in patients with metastatic renal cell carcinoma reported an objective response rate of 33.3%. ecancer.orgcancerchoices.org Another study investigating this compound in combination with human lymphoblastoid interferon-alpha in patients with advanced renal cell carcinoma reported an objective response rate of 41%. ecancer.orgcancerchoices.org

In melanoma, investigation of this compound as a monotherapy in metastatic melanoma was explored in small Phase II trials. nih.gov One trial involving previously untreated patients with metastatic melanoma treated with oral this compound observed objective responses in a subset of patients, including one long-lasting complete response. nih.gov However, later studies investigating this compound in combination with immunotherapy approaches in metastatic melanoma did not demonstrate significant differences compared to non-cimetidine arms. nih.govascopubs.org Despite mixed results, this compound's potential role in melanoma, possibly through immunomodulatory effects by blocking histamine activation of suppressor T-cells, continues to be explored. iastate.edu

Breast Cancer Models and T-Cell Response Modulation

Research in breast cancer models has investigated this compound's ability to modulate T-cell responses. Studies using a breast cancer model in Balb/c mice, established with the 4T1 cell line, explored the effects of this compound and ibuprofen, alone and in combination, on T cell-related parameters. waocp.orgnih.govnih.gov Untreated cancerous mice showed a lower percentage of splenic Th1 cells and plasma IFN-γ levels, along with a higher percentage of splenic Treg cells and plasma TGF-β levels compared to healthy mice. waocp.orgnih.govnih.gov Treatment with this compound, ibuprofen, or their combination increased the frequency of Th1 cells and IFN-γ levels while reducing the frequencies of Treg cells and TGF-β levels in BC-bearing mice. waocp.orgnih.govnih.gov Specifically, this compound treatment resulted in a significant reduction in the percentage of splenic Treg cells compared to untreated cancerous mice (P<0.02). waocp.orgnih.gov The combination of this compound and ibuprofen also significantly increased T-bet expression compared to untreated mice (P<0.006). waocp.orgnih.govnih.gov this compound and/or ibuprofen treatment also reduced intra-tumoral expression of FOXP3 and RORγt. waocp.orgnih.govnih.gov These findings suggest that this compound can influence the balance of T-cell subsets in the context of breast cancer models, potentially enhancing anti-tumor immunity.

Table 1: Effects of this compound and Ibuprofen on T-Cell Parameters in a Mouse Breast Cancer Model

Note: P-values indicate statistical significance compared to untreated cancerous mice. "Increased" or "Reduced" without P-values indicate observed trends.

Combination Therapies in Oncology Research

This compound has been investigated in combination with other therapies in oncology research, particularly in colorectal cancer and malignant melanoma. Some clinical studies have indicated that this compound may offer a survival benefit in patients with colorectal cancer after surgical resection. nih.govpharmacytimes.com Preclinical evidence suggests this benefit might extend to other cancer types. pharmacytimes.com The potential anti-cancer effects of this compound are thought to involve various mechanisms, including immunomodulation, inhibition of cancer cell proliferation, effects on histamine metabolism, blocking E-selectin expression to inhibit cancer cell adhesion and prevent metastasis, and inhibiting angiogenesis. nih.gov

In malignant melanoma, a provocative report suggested a potential role for this compound, an inhibitor of suppressor T cell function, in managing disseminated malignant melanoma. ascopubs.org A phase II study evaluating single-agent this compound in patients with advanced malignant melanoma reported one complete response and two partial regressions among 19 patients. ascopubs.org Another study involving patients who received interferon-alpha and oral this compound reported objective regressions, although the respective contributions of each drug were not determined. ascopubs.org

Molluscum Contagiosum and Viral Warts

This compound has been investigated as a treatment for molluscum contagiosum and viral warts, particularly in children. escholarship.orgnih.govmatheny.infoaafp.orgkoreamed.org Some open trials and case reports suggested a benefit of oral this compound for molluscum contagiosum and viral warts. matheny.infoaafp.orgjwatch.org For molluscum contagiosum, one study in children reported clearance of lesions in a significant proportion of patients treated with oral this compound. jwatch.org However, other studies, including double-blind, placebo-controlled trials, have not found this compound to be significantly more effective than placebo for clearing molluscum contagiosum. escholarship.orgmatheny.infodrugbank.comdroracle.ai

Similarly, for viral warts, while some studies indicated potential effectiveness, particularly in children, double-blind, placebo-controlled studies have yielded conflicting results, with some showing no statistically significant superiority over placebo. escholarship.orgmatheny.infoaafp.org A trend toward efficacy in younger patients has been suggested. matheny.infoaafp.org One promising area of research is the use of this compound in conjunction with other therapies for warts. escholarship.orgaafp.org A combination regimen of this compound and levamisole was reported to be superior to this compound alone in treating warts in adults and children. escholarship.orgaafp.org

Urticaria and Mastocytosis

This compound appears to have a role in the treatment of chronic idiopathic urticaria and some other types of urticaria when used in combination with various H1 blockers. escholarship.orgdrugbank.com The combination of an antihistamine and an H2 antagonist, such as chlorpheniramine and this compound, appears to be effective for symptomatic dermatographism. escholarship.orgdrugbank.com Studies have shown that the combination of H1 and H2 receptor antagonists can improve clinical outcomes in patients with acute urticaria symptoms compared to using either antagonist alone. mdpi.com For chronic idiopathic urticaria, the addition of this compound has been effective in some patients who did not completely respond to adequate doses of H1 blockers. mdpi.comresearchgate.net

In systemic mastocytosis, this compound has been used to manage symptoms. nih.govdrugbank.com A case report described a patient with systemic mastocytosis and gastric hypersecretion treated with this compound, which resulted in the healing of a duodenal ulcer and marked amelioration of cutaneous symptoms. nih.gov This suggests that some cutaneous symptoms of mastocytosis may be mediated via histamine H2 receptors in the skin. nih.gov

Atopic Dermatitis: Immune System Modulation

Research has explored this compound as an adjuvant therapy for atopic dermatitis, particularly acute-extrinsic atopic dermatitis, due to its potential immunomodulatory effects. researchgate.netclinicaltrials.eunih.gov this compound is believed to modulate the immune system by activating Th1 responses and lowering Th2 activity, as well as potentially reducing IgE levels, which may help decrease the severity of atopic dermatitis symptoms. researchgate.netclinicaltrials.eu

A double-blind randomized controlled trial involving patients with acute extrinsic atopic dermatitis assessed the effectiveness of this compound as an adjuvant to standard treatment. researchgate.netnih.gov Significant differences were observed in SCORing Atopic Dermatitis (SCORAD) and objective SCORAD changes in the group receiving this compound compared to the control group at various time points. researchgate.netnih.gov Significant changes in IgE levels were also noted in the this compound group. researchgate.netnih.gov However, there were no significant changes in IFN-γ, IL-12, and IL-4 levels between the groups in this specific study. researchgate.netnih.gov

Table 2: Effects of this compound as Adjuvant Therapy in Acute-Extrinsic Atopic Dermatitis

Erythropoietic Protoporphyria and X-linked Protoporphyria

This compound has gained attention as a possible treatment for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), collectively known as the protoporphyrias. nih.govporphyria.orgcenterwatch.comresearchgate.netdrugbank.comresearchgate.net These genetic disorders of heme biosynthesis lead to the accumulation of protoporphyrin IX (PPIX), causing severe photosensitivity. porphyria.orgcenterwatch.comresearchgate.netresearchgate.net

The potential role of this compound in treating protoporphyrias is based on the hypothesis that it might inhibit delta-aminolevulinate synthase (ALAS), the first enzyme of heme biosynthesis, thereby reducing PPIX production. centerwatch.comresearchgate.net This inhibitory effect was initially observed in vitro. centerwatch.com Case reports have anecdotally suggested a benefit in EPP. centerwatch.com

An FDA-sponsored research study is currently assessing whether oral this compound administration reduces PPIX levels and impacts photosensitivity in patients with EPP or XLP. porphyria.orgcenterwatch.com This study is a prospective, blinded, randomized, 2x2 cross-over trial comparing this compound to placebo. centerwatch.com Efficacy is being evaluated based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. centerwatch.com A recent study in Denmark also indicated the potential for this compound to lower PPIX in patients with EPP. porphyria.org While some reports have described apparent beneficial effects, concerns have been raised regarding the evidence base, highlighting the need for controlled studies. researchgate.net

Research in Herpesvirus Infections

Small studies have investigated the use of this compound in patients with herpesvirus infections, including herpes simplex virus (HSV) and herpes zoster. jmir.org this compound has also been explored for its possible antiviral effect in measles, another viral infection, with one study suggesting it might provide a sooner recovery from symptoms. mikrobiyolbul.org While some reports suggest this compound can treat patients with chronic Epstein-Barr virus (EBV) reactivation, its efficacy in associated neurological disorders has not been confirmed. frontiersin.org this compound has also been mentioned in the context of drug interactions with antiviral medications like famciclovir, used for herpesvirus infections. tandfonline.com In some studies involving the treatment of chronic fatigue syndrome potentially linked to herpesviruses, this compound was sometimes administered alongside antiviral therapy (like acyclovir or valacyclovir) to potentially increase serum levels of the antiviral by inhibiting tubular secretion. dovepress.comscholaris.ca

Investigational Use in Viral Infections (e.g., SARS-CoV-2)

Given prior evidence of antiviral activity against other viruses, including anti-SARS-CoV activity, this compound has been considered for investigational use in viral infections such as SARS-CoV-2. researchgate.net The potential for repurposing existing drugs like this compound for urgent clinical needs, such as the COVID-19 pandemic, has been highlighted due to their established safety profiles, affordability, and accessibility. jmir.orgjmir.org

Molecular Docking and Dynamics Studies with Viral Proteins

Molecular docking studies have been conducted to explore the potential interaction of this compound with SARS-CoV-2 viral proteins. These studies aim to understand the molecular basis for any potential efficacy against the virus. Molecular docking results have shown that this compound, along with other H2 receptor antagonists like famotidine, can bind to SARS-CoV-2 structural proteins. researchgate.net Specifically, studies involving molecular docking and dynamics simulations have suggested that this compound could inhibit SARS-CoV-2 replication by binding to non-structural proteins, including NSP3, NSP7/8 complex, and NSP9. researchgate.netnih.gov Results from these in silico studies indicated that this compound exhibited a higher binding affinity to these viral proteins compared to other H2RAs like nizatidine and ranitidine. researchgate.netnih.gov Molecular dynamic simulations further revealed that this compound binds to these non-structural proteins with high stability over a simulated period of 100 nanoseconds. researchgate.netnih.gov The ability of this compound to bind NSP3 may potentially prevent this protein from acting as a scaffold, thereby hindering its interaction with itself and other viral NSPs and potentially halting viral replication. nih.gov Kinase enrichment analysis has also predicted the involvement of genes such as ERKs, SMADs, and MAPKs in the potential antiviral activity of this compound against SARS-CoV-2. researchgate.net

Data from Molecular Docking and Dynamics Studies (Illustrative Example based on search results):

Note: Specific numerical binding affinity values varied across different studies and methods. The table above summarizes the comparative findings. researchgate.netnih.gov

Stress Ulcer Prophylaxis Research

Research has explored the use of this compound for stress ulcer prophylaxis, particularly in high-risk patients such as those in intensive care units or those with severe burns. cochranelibrary.comdtic.mil Stress-induced ulcers, like Curling's ulcers in burn patients, are related to a defect in the mucosal barrier often exacerbated by ischemia, hypotension, sepsis, and hypoxia. dtic.mil Early prophylactic administration of this compound, sometimes in combination with antacids, has been shown to significantly reduce the occurrence of complications from these lesions. dtic.mil Experimental studies, including those in rats, have indicated that this compound can prevent the occurrence of stress ulcers. journals.co.za While this compound and other H2-antagonists fulfill many criteria for an ideal stress ulcer prophylaxis drug, clinically significant bleeding can still occur during their use. google.com Studies have compared this compound to other agents like sucralfate for stress ulcer prophylaxis in specific patient populations, such as thermally injured patients. google.com

Data from a Stress Ulcer Prophylaxis Study (Illustrative Example based on search results):

Note: This table represents findings from experimental studies where this compound showed a decrease in stress ulcer occurrence compared to control groups. journals.co.za

Interstitial Cystitis/Bladder Pain Syndrome: Histamine Receptor Blockade in Bladder Wall

This compound, as a histamine H2-receptor antagonist, has been investigated for the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), a chronic condition characterized by bladder pain or discomfort in the absence of infection. uspharmacist.comemjreviews.comfrontiersin.org The rationale for using this compound in IC/BPS is based on the theory that histamine plays a role in the pathophysiology of the condition, potentially through its effects on the bladder wall. uspharmacist.comemjreviews.com Increased numbers of activated bladder mast cells, which release inflammatory mediators like histamine, have been repeatedly reported in patients with IC/BPS. By blocking histamine H2 receptors, this compound aims to mitigate the effects of histamine in the bladder wall. uspharmacist.comemjreviews.com Evidence supporting the use of this compound in IC/BPS comes from small observational trials and randomized controlled trials. uspharmacist.comemjreviews.com Studies have reported that this compound was statistically significant compared to placebo in improving total symptoms, including pain and nocturia, after several months of treatment. uspharmacist.com Observational studies have also indicated that a percentage of patients report clinically significant improvement in symptoms with this compound. uspharmacist.com While some studies showed symptom relief, histological changes in the bladder mucosa were not consistently observed.

Data from Interstitial Cystitis/Bladder Pain Syndrome Studies (Illustrative Examples based on search results):

Study 1: Randomized Controlled Trial uspharmacist.com

Study 2: Observational Studies uspharmacist.com

Impact on Metabolism of Co-administered Drugs via CYP Inhibition

This compound is a potent inhibitor of several cytochrome P450 (CYP) enzymes in the liver. mdedge.comwikipedia.orgnih.gov This inhibition is often competitive and reversible, although mechanism-based irreversible inhibition has also been identified for certain isoforms like CYP2D6. wikipedia.org By inhibiting these enzymes, this compound can reduce the metabolic clearance of drugs that are substrates for these CYP isoforms, leading to increased plasma concentrations and potentially enhanced pharmacological effects or toxicity. drugbank.commdedge.comnih.gov The primary CYP isoforms inhibited by this compound include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, with notable inhibition of CYP1A2, CYP2D6, and CYP3A4. wikipedia.org

Specific Examples: Warfarin, Theophylline, Phenytoin, Carbamazepine, Opioid Analgesics, Tricyclic Antidepressants, Lidocaine, Benzodiazepines, Ketoconazole, Itraconazole, Tamoxifen, Codeine, Tramadol

This compound's CYP inhibitory effects lead to clinically significant interactions with numerous drugs:

Warfarin: this compound inhibits the hepatic metabolism of warfarin, particularly the less potent R-warfarin enantiomer, which can increase its anticoagulant effect. mdedge.comnih.govdrugs.comdrugs.com This interaction necessitates monitoring of prothrombin time or International Normalized Ratio (INR) when co-administered. drugs.com

Theophylline: this compound significantly reduces the clearance of theophylline, a substrate of CYP1A2, leading to increased serum concentrations and potential toxicity. mdedge.comwikipedia.org

Phenytoin: this compound has been shown to increase steady-state phenytoin concentrations by inhibiting its metabolism, likely through CYP inhibition. mdedge.com

Carbamazepine: this compound can enhance the metabolism of opioids that rely on hepatic metabolism, and carbamazepine is listed among drugs whose metabolism can be affected. nih.gov

Opioid Analgesics: this compound may increase the effects of opioid analgesics by increasing their duration of action, primarily through inhibition of CYP enzymes involved in their metabolism, such as CYP3A4. nih.govdovepress.com

Tricyclic Antidepressants: this compound can elevate the levels of tricyclic antidepressants like imipramine and nortriptyline by inhibiting their metabolism (demethylation and hydroxylation), increasing the likelihood of adverse effects. wikipedia.orgstatpearls.comnih.gov

Lidocaine: this compound can alter the metabolism of lidocaine, leading to increased plasma concentrations. mdedge.comnih.gov

Benzodiazepines: this compound can decrease the metabolism of certain benzodiazepines, such as alprazolam and bromazepam, potentially increasing their serum levels and effects by affecting CYP3A4 metabolism. mdedge.comwikipedia.orgmedscape.com

Ketoconazole and Itraconazole: this compound reduces the absorption of these antifungal agents because they require a low gastric pH for dissolution and absorption, and this compound increases gastric pH. mdedge.comwikipedia.org

Tamoxifen: this compound may decrease the effects of tamoxifen, which is a prodrug activated by CYP2D6, by inhibiting its metabolism to the active metabolite. wikipedia.org

Codeine: this compound can increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism, which is responsible for converting codeine to its active metabolite, morphine. wikipedia.orgmedscape.comdrugbank.com This can prevent the conversion of codeine to morphine. medscape.com

Tramadol: Similar to codeine, this compound may decrease the effects of tramadol, a prodrug metabolized by CYP2D6, by inhibiting its activation. wikipedia.org

Influence on Renal Excretion of Other Drugs (e.g., Metformin, Procainamide)

This compound can also interfere with the renal excretion of certain drugs by inhibiting renal tubular transport mechanisms. drugbank.commdedge.com This primarily involves competitive inhibition of organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters in the renal tubules, which are responsible for the active secretion of cationic drugs into the urine. drugbank.commdpi.comnih.govacs.org

Metformin: this compound inhibits the renal excretion of metformin, a substrate for OCT2 and MATE transporters, leading to increased circulating levels of metformin. wikipedia.orgmdpi.comnih.govacs.orgnih.gov Studies have shown a significant increase in metformin plasma concentrations and a reduction in its renal clearance when co-administered with this compound. nih.govnih.gov This interaction is considered a classical example of a renal cation transporter-mediated drug-drug interaction. acs.org

Procainamide: this compound inhibits the renal clearance of procainamide, which is secreted by an active transport mechanism in the proximal tubule. mdedge.comnih.govnih.govnih.gov This inhibition can lead to increased plasma concentrations and decreased renal clearance of procainamide and its metabolite, N-acetylprocainamide. nih.govnih.gov

Effects on Gastric pH and Drug Absorption Alterations

As an H2 receptor antagonist, this compound reduces gastric acid secretion, leading to an increase in gastric pH. nih.govpatsnap.comnih.gov This alteration in gastric pH can affect the absorption of drugs whose solubility or stability is pH-dependent. medscape.compatsnap.comnih.gov

For drugs that require an acidic environment for dissolution and absorption (e.g., ketoconazole, itraconazole), the increased gastric pH caused by this compound can lead to decreased absorption and reduced bioavailability. mdedge.comwikipedia.orgnih.govacs.org Conversely, the absorption of some drugs whose absorption is normally decreased by acid inactivation in the stomach might be increased. nih.gov However, the clinical significance of this compound's effect on gastric pH on drug absorption has not always been definitively established for all interacting drugs. nih.gov

Potential Attenuation of Anti-PD-1/PD-L1 Therapeutic Effects

Studies suggest that this compound may have the potential to attenuate the therapeutic effects of anti-PD-1 and anti-PD-L1 therapies, which are a class of immune checkpoint inhibitors used in cancer treatment. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1) pathway is a critical immune checkpoint that, when activated, suppresses T-cell function, allowing cancer cells to evade immune surveillance. Inhibitors targeting this pathway aim to restore anti-tumor immunity. frontiersin.orgwikipedia.orgexplorationpub.com

Research in colon cancer models has investigated the combined effects of this compound with anti-PD-1 and anti-PD-L1 antibodies. In an in vivo study using BALB/c mice implanted with CT26 colon adenocarcinoma cells, while anti-PD-1 and anti-PD-L1 suppressed tumor growth, this compound showed only mild anti-tumor activity on its own. researchgate.netnih.govnih.gov Crucially, when this compound was administered in combination with either anti-PD-1 or anti-PD-L1, it significantly attenuated their anti-tumor effects. researchgate.netnih.govnih.gov

Further investigation into the tumor microenvironment revealed that anti-PD-L1 treatment increased the presence of CD3+, CD4+, and CD8+ T cells, as well as M1 macrophages, all of which are associated with anti-tumor immunity. researchgate.netnih.gov However, combined treatment with this compound reversed this increase in these immune cell populations. researchgate.netnih.gov this compound also reversed the decrease in circulating and tumor-associated neutrophils induced by anti-PD-1 and anti-PD-L1, suggesting a modulation of the immune cell landscape that may counteract the effects of checkpoint inhibition. researchgate.netnih.gov

The mechanism underlying this attenuation is not fully elucidated but may involve this compound's interference with histamine-mediated immunomodulation, potentially through its action on histamine H2 receptors which are present on various immune cells. researchgate.netnih.govnih.gov

Antiandrogenic and Estrogenic Activities: Research on Hormonal Axes

This compound exhibits weak antiandrogenic activity, primarily through its ability to competitively antagonize the androgen receptor (AR), the target of androgens like testosterone and dihydrotestosterone (DHT). wikipedia.orgnih.govoup.com Although its affinity for the AR is considerably weaker than that of endogenous androgens, this interaction can lead to antiandrogenic effects, particularly at higher doses or during long-term treatment. wikipedia.orgnih.gov

Research also indicates that this compound can influence estrogen levels. This effect is thought to be primarily mediated by the inhibition of cytochrome P450 enzymes involved in the metabolism of estradiol, specifically inhibiting the 2-hydroxylation of estradiol in the liver. wikipedia.orgajol.inforesearchgate.net This inhibition can lead to decreased degradation of estradiol and consequently increased serum estradiol levels. wikipedia.orgajol.inforesearchgate.net An additional proposed mechanism for increased estradiol levels is the potential for increased conversion of testosterone to estrogen, particularly in the presence of elevated testosterone levels induced by this compound treatment. ajol.info

The interplay between these antiandrogenic and estrogenic effects can contribute to hormonal imbalances.

Effects on Testosterone Biosynthesis and Estradiol Hydroxylation

Studies have investigated the direct effects of this compound on testosterone biosynthesis and estradiol hydroxylation. While some reports suggest this compound may reduce testosterone biosynthesis in individual cases, the primary impact appears to be related to its antiandrogenic properties and effects on estradiol metabolism. wikipedia.orgaacrjournals.org

Inhibition of estradiol 2-hydroxylation by this compound has been demonstrated, leading to increased serum estradiol concentrations. wikipedia.orgajol.inforesearchgate.net This mechanism is considered a significant factor in the observed estrogenic effects of this compound. wikipedia.orgajol.inforesearchgate.net

Research in male rats administered this compound showed a significant increase in serum testosterone levels, alongside increases in FSH and estradiol. ajol.info This increase in testosterone is potentially linked to the antiandrogenic properties of this compound, which may lead to a loss of negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby stimulating gonadotropin release (like LH and FSH) which, in turn, can increase testosterone production. wikipedia.orgajol.info However, other studies in male rats have reported decreased testosterone levels with this compound treatment, highlighting variability in findings potentially related to dose and study duration. ijpbms.com

Prolactin Level Modulation

This compound has been associated with increased serum prolactin levels. wikipedia.orgaacrjournals.orgnih.govijpbms.com This effect is thought to be related to its action as a histamine H2 receptor antagonist, as H2 receptors are involved in the regulation of prolactin secretion. nih.govijpbms.comdovepress.com High doses of this compound have been particularly linked to elevated prolactin levels. nih.govijpbms.com

Studies in healthy volunteers have shown that intravenous administration of this compound can acutely raise serum prolactin levels. researchgate.netnih.gov The mechanism may involve a reduced dopaminergic inhibition of pituitary lactotrophs, the cells responsible for prolactin production, as dopamine is a known inhibitor of prolactin release. researchgate.netnih.gov

Research on Reproductive System Effects in Male Models

Research in male animal models, particularly rats, has provided insights into the effects of this compound on the reproductive system. This compound has been classified as a reproductive toxicant in male rats, with studies documenting adverse effects on testicular structure and function. idosr.orgoup.comoup.comresearchgate.netnih.gov

Observed effects in male rat models include decreased sperm motility, count, and viability, as well as an increase in abnormal sperm morphology. ijpbms.comidosr.org Histological examinations of testicular tissue have revealed structural abnormalities, such as degeneration of seminiferous tubules, reduced tubular diameter, and increased apoptotic germ cells. idosr.orgoup.comoup.comresearchgate.netnih.gov

The mechanisms underlying this compound-induced reproductive toxicity in male models are complex and may involve multiple factors, including hormonal imbalances, direct effects on testicular cells (such as peritubular cells), and induction of apoptosis. idosr.orgoup.comoup.comresearchgate.netnih.govspandidos-publications.com

Here is a summary of some research findings on this compound's effects on hormone levels in male models:

Note: This table summarizes findings from different studies with varying methodologies and may not represent a direct comparison across all parameters within a single study. ajol.infoijpbms.comoup.comnih.govspandidos-publications.comnih.govumich.edu

Testicular Histoarchitecture Alterations

Research indicates that this compound administration negatively impacts the structural integrity of the testes, leading to significant histopathological changes. Studies in male rats have observed considerable alterations in testicular histoarchitecture, including distortions in the seminiferous tubules idosr.orgnih.gov. These structural changes can involve the degeneration of seminiferous tubules, which are crucial for supporting normal spermatogenesis oup.comoup.com. Histological examinations have revealed irregular tubules, disordered epithelium, and intraepithelial vacuolization oup.comresearchgate.net. Furthermore, a reduction in tubular diameter and epithelial area has been noted, attributed to the detachment and loss of germ cells elsevier.es.

Studies have also pointed to effects on the peritubular tissue. Reduced peritubular tissue volume and the presence of apoptotic peritubular cells suggest that these cells are a primary target of this compound toxicity oup.comresearchgate.netoup.com. Investigations have also demonstrated that this compound can induce testicular microvasculature atrophy, characterized by a significant decrease in microvascular density and vascular luminal area, along with collapsed blood vessel profiles elsevier.esnih.govresearchgate.netresearchgate.net. This vascular impairment is thought to contribute to the structural disruption of the seminiferous tubules elsevier.es.

Spermatogenesis Impairment and Apoptosis Induction

This compound has been shown to impair spermatogenesis, the process of sperm production, in male subjects and animal models. This impairment is closely linked to the observed histoarchitecture alterations and the induction of apoptosis in various testicular cell populations. Studies have reported significant declines in sperm count, motility, and morphology in men treated with this compound oup.comresearchgate.net. In rat models, this compound administration has resulted in decreased sperm quality, including reduced sperm motility and count idosr.orgnih.govelsevier.es.

The drug is recognized as an inducer of apoptosis, a programmed cell death mechanism, in testicular cells oup.com. Apoptotic changes have been highlighted in peritubular cells and spermatogenic cells oup.comresearchgate.net. The loss of germ cells by apoptosis contributes to the reduction in the epithelial area of the seminiferous tubules elsevier.es. TUNEL labeling, a technique to detect apoptotic cells, has confirmed extensive apoptotic cell death in peritubular cells and vascular smooth muscle cells within the testes of this compound-treated rats oup.comnih.govresearchgate.netnih.gov. This apoptosis in vascular cells leads to testicular vascular atrophy nih.govresearchgate.netresearchgate.net.

Studies have also observed maturation arrest of spermatogenic cells idosr.orgresearchgate.net. The impairment of peritubular cells, which provide structural and nutritional support for developing sperm, and the apoptosis of spermatogenic cells contribute to compromised sperm production oup.comresearchgate.net.

Below is a table summarizing some research findings on the effects of this compound on sperm parameters:

Hormonal Imbalance in Male Reproductive Axis

This compound can disrupt the delicate balance of the hypothalamic-pituitary-testicular axis, a key regulator of male reproductive function, leading to hormonal imbalances oup.comoup.comresearchgate.net. Studies have documented alterations in the levels of key reproductive hormones.

Research in male rats has shown that this compound administration can lead to changes in hormonal levels, confirming an antiandrogenic effect elsevier.esunesp.br. Some studies have reported elevated luteinizing hormone (LH) and testosterone levels idosr.orgresearchgate.net. However, other research indicates concurrently reduced levels of follicle-stimulating hormone (FSH) and testosterone oup.comoup.com. In one study on men, testosterone levels were found to be elevated during therapy, while serum LH remained unchanged and FSH was increased nih.gov. Some individual case reports suggest that this compound may reduce testosterone biosynthesis and increase prolactin levels, potentially secondary to increased estrogen levels wikipedia.org. At typical therapeutic levels, this compound may have no effect or cause small increases in circulating testosterone, possibly due to the loss of negative feedback on the HPG axis resulting from androgen receptor antagonism wikipedia.org.

This compound is known to exert antiandrogenic effects by antagonizing androgen receptors and potentially inhibiting the conversion of testosterone to dihydrotestosterone (DHT) oup.comresearchgate.net. This interference with androgen signaling pathways can impair spermatogenesis and contribute to reduced sperm quality oup.comresearchgate.net.

Below is a table summarizing some research findings on the effects of this compound on male reproductive hormones:

In Vitro Studies (e.g., Cell Adhesion Assays, Microsomal Studies)

In vitro studies utilize isolated biological components, such as cells or enzymes, to investigate specific interactions with this compound. Cell adhesion assays, for instance, can be used to explore this compound's potential effects on cellular interactions, which is relevant in contexts like cancer metastasis. Microsomal studies are crucial for understanding how this compound interacts with drug-metabolizing enzymes, particularly cytochrome P-450 (CYP) enzymes, in the liver.

Early in vitro studies using rat hepatic microsomes indicated that this compound, at millimolar concentrations, could inhibit various CYP-mediated enzyme activities in a seemingly reversible manner. ubc.ca However, these concentrations were significantly higher than typical serum concentrations observed in both rats and humans. ubc.ca More detailed in vitro investigations have shown that this compound can inhibit the O-deethylation of 7-ethoxycoumarin in rat liver microsomes. nih.gov This inhibition was more pronounced when this compound was preincubated with the microsomes in the presence of an NADPH-generating system before the substrate was added. nih.gov This preincubation also led to a decrease in cytochrome P-450 content, suggesting the involvement of an activated complex with the enzyme. nih.gov Studies have also explored the effect of this compound on specific CYP isoforms like CYP1A1 and CYP2C6 in rat hepatic microsomes. medicinacomplementar.com.br Preincubation of microsomes from uninduced rats with this compound and NADPH in vitro increased the potency of inhibition of EROD activity by 20-fold, suggesting that this compound inhibits CYP2C6 by forming a metabolite/intermediate complex, similar to its interaction with CYP2C11. medicinacomplementar.com.br

In the context of cancer research, in vitro studies have examined the direct effects of this compound on cancer cell lines. For example, studies on colon adenocarcinoma CT26 cells investigated the impact of this compound on cell viability, clonogenicity, and cell cycle distribution. nih.gov An MTT assay was used to measure mitochondrial activity and estimate cell viability. nih.gov While this compound did not show a significant effect on cell viability in this specific cell line, it did significantly affect clonogenicity. nih.gov

In Vivo Animal Models (e.g., Mouse Models for Cancer, Rat Models for Reproductive Toxicity, Pharmacokinetics)

In vivo studies using animal models are essential for evaluating the systemic effects of this compound, including its pharmacokinetics, efficacy in complex biological systems, and potential toxicity to various organs.

Mouse and rat models have been extensively used to investigate the potential anti-cancer effects of this compound, often focusing on its immunomodulatory mechanisms. nih.gov Early in vivo results suggested that this compound could enhance the cytotoxic effect of cyclophosphamide in male DBA2 mice injected with P-388 leukaemia cells, leading to a significant increase in survival time. nih.gov However, some challenges in replicating these early findings were reported. nih.gov Research has continued to explore this compound's effects, often in combination with other agents, in various cancer types in animal models, including melanoma, ovarian cancer, colorectal cancer, gastric tumors, pancreatic cancer, lung cancer, and gliomas. nih.gov Additionally, studies in mouse and rat models of bladder cancer have indicated that the anti-angiogenic effect of this compound administration may be linked to reduced expression of platelet-derived endothelial growth factor (PDECGF) and VEGF. nih.gov

Rat models have also been utilized to study the potential reproductive toxicity of this compound. Studies involving oral administration of this compound to male rats at different doses for several weeks have assessed its effects on the reproductive system. researchgate.net Parameters evaluated include sperm parameters (count, viability, morphology) using computer-assisted sperm analysis, serum hormone levels (testosterone, FSH, LH) measured by ELISA, and histological examination of the testes. researchgate.net Findings from such studies have indicated that this compound can lead to a significant decrease in sperm motility, an increase in abnormal sperm morphology, and a decrease in sperm counts at certain doses. researchgate.net Histological examination has revealed testicular lesions, including increased thickness of epithelial cells and diameter of seminiferous tubules, and a reduction in Leydig's cells. researchgate.net

Pharmacokinetic studies in animals help to understand how this compound is absorbed, distributed, metabolized, and excreted. Studies in rats and dogs have shown that the principal metabolite of this compound is the sulfoxide, formed by oxidation of the side-chain sulfur. iarc.fr In rats, this compound has been shown to inhibit hepatic CYP2C6 and CYP2C11 in vivo but not CYP1A1. medicinacomplementar.com.br

Molecular Docking and Molecular Dynamics Simulations

Computational methods like molecular docking and molecular dynamics simulations play a vital role in understanding the interactions between this compound and its target molecules at an atomic level. These techniques can predict binding affinities, identify key interaction sites, and simulate the dynamic behavior of drug-receptor complexes.

Molecular docking studies have been used to investigate the binding of this compound to the human histamine H2 receptor, its primary target. scialert.netbenthamscience.com These studies aim to define the binding sites and identify key amino acid residues involved in the interaction. scialert.netbenthamscience.com For example, Asp98 in transmembrane domain 3 (TM3) has been identified as a major contributor to ligand binding through hydrogen bond interactions. scialert.netbenthamscience.com Asn159 in TM4 and Asp186 in TM5 have also been found to be important in stabilizing the H2 receptor-antagonist complex. benthamscience.com

Molecular dynamics simulations complement docking studies by providing insights into the stability of the drug-receptor complex over time and the conformational changes that occur upon binding. scialert.netbenthamscience.comnih.gov Simulations of this compound bound to the H2 receptor have been performed to validate homology models of the receptor and assess the reliability of docking results. scialert.netbenthamscience.com

More recently, molecular docking and dynamics simulations have been applied to explore the potential of this compound for repurposing against other targets, such as proteins from the SARS-CoV-2 virus. nih.gov Studies have performed molecular docking between this compound and viral non-structural proteins (NSP3, NSP7/8 complex, and NSP9) to assess binding affinity. nih.gov Subsequent molecular dynamics simulations over 100 ns have been conducted to evaluate the stability of the complexes and the efficiency of binding. nih.gov Results from such studies have suggested that this compound could bind to these non-structural proteins with high stability. nih.gov

Randomized Controlled Trials

Randomized controlled trials (RCTs) are considered the gold standard for evaluating the efficacy of interventions. In RCTs, participants are randomly assigned to receive either this compound or a control (e.g., placebo or another treatment) to minimize bias and allow for robust comparisons of outcomes.

RCTs have been conducted to assess the effectiveness of this compound in treating conditions like dyspepsia, peptic ulcers, and oesophagitis. nih.govtandfonline.com Studies have utilized double-blind, placebo-controlled designs, including single-subject trials and multi-crossover designs, to evaluate the symptomatic relief provided by this compound. nih.govtandfonline.com These trials have shown that this compound can significantly alleviate symptoms compared to placebo in patients with peptic ulcer disease, oesophagitis, and non-ulcer dyspepsia. tandfonline.com

RCTs have also investigated the potential role of this compound in cancer treatment. A randomized, double-blind, placebo-controlled trial by the British Stomach Cancer Group examined the effects of this compound on the survival of patients with gastric cancer. researchgate.net The study randomized patients with early and advanced gastric cancer to receive either this compound or placebo. researchgate.net The primary endpoint was death. researchgate.net

Another area of investigation using RCTs is the potential for this compound in weight management. An open, non-randomized follow-up study of subjects who had completed an 8-week randomized double-blind, placebo-controlled trial of this compound for weight loss explored the long-term effects of intermittent this compound treatment combined with diet and exercise. medscimonit.com

Systematic Reviews and Meta-Analyses

Systematic reviews and meta-analyses synthesize findings from multiple individual studies to provide a comprehensive and often more precise estimate of an intervention's effect. Systematic reviews follow a rigorous process to identify, evaluate, and summarize relevant research, while meta-analyses use statistical methods to combine data from multiple studies.

Systematic reviews have been conducted to assess the evidence for repurposing this compound as a potential immunomodulatory agent against colorectal carcinoma. nih.gov These reviews typically search electronic databases for relevant RCTs that investigated the effects of this compound on survival and immunomodulation, such as improvements in tumor-infiltrating lymphocytes (TILs) and peripheral blood lymphocytes. nih.gov Findings from such reviews have indicated that this compound may offer a survival benefit and exhibit immunomodulatory effects in patients undergoing curative resection for colorectal cancer, although the heterogeneity of studies highlights the need for large-scale, well-designed prospective RCTs. nih.gov

Meta-analyses have also been performed to compare the efficacy of this compound with other treatments for various conditions. For instance, a meta-analysis compared the efficacy of this compound and ribavirin in the treatment of mumps by analyzing controlled trials. bbwpublisher.com The analysis evaluated outcomes such as effective rate and time of swelling regression. bbwpublisher.com Another meta-analysis pooled data from randomized, double-blind, placebo-controlled trials to determine the frequency of adverse reactions among patients treated with this compound for acute acid-peptic disorders. nih.gov

Systematic reviews have also been used to consolidate research findings on the potential of medicinal plants to restore reproductive functionality following this compound-induced reproductive toxicity, assessing their effectiveness, safety, and mechanisms. oup.comoup.com

Here is a summary of some research findings discussed:

Observational Studies and Real-World Evidence

Observational studies and the analysis of Real-World Evidence (RWE) play a crucial role in understanding the usage and potential effects of this compound in diverse patient populations and routine clinical practice settings. RWE is clinical evidence derived from the analysis of Real-World Data (RWD), which is collected from various sources outside of traditional randomized controlled trials (RCTs). frontiersin.orgfda.gov These sources can include electronic health records, disease registries, and claims databases. frontiersin.org

While RCTs are considered the gold standard for establishing efficacy and safety under controlled conditions, RWE offers valuable insights into the performance of drugs in broader, more heterogeneous populations encountered in everyday healthcare. dovepress.com This is particularly relevant for a widely used and long-standing drug like this compound. Observational studies can help assess long-term outcomes, identify potential safety signals, and evaluate the effectiveness of this compound in subgroups of patients who might not be well-represented in clinical trials. dovepress.com

For instance, RWE has been utilized in pharmacovigilance to monitor and quantify adverse drug effects. It can also inform study design and provide insights into the efficacy and safety of health products in real-world settings. frontiersin.org The greatest strength of RWE studies lies in their external validity, allowing for the evaluation of treatment transferability to broader populations.

However, it is important to acknowledge the limitations of observational studies, including the potential for confounding, selection bias, and information bias, especially when attempting to establish causality. Despite these challenges, RWE studies contribute valuable data that complements findings from controlled trials, providing a more comprehensive understanding of this compound's impact in the real world.

Heterogeneity in Study Designs

A significant challenge in synthesizing findings from different this compound studies is the considerable heterogeneity in study designs. This variability can manifest in various aspects, including patient populations, treatment durations, dosages (though dosage information is excluded here), and outcome measures. For example, studies investigating the effect of this compound on blood alcohol levels have been criticized for issues such as small sample sizes, heterogeneity of study populations, and variations in the amount and timing of alcohol ingestion, as well as participants' fed or fasted status. nih.gov

Repurposing in Oncology and Immune-Related Diseases

One of the most active areas of emerging research for this compound is its potential for repurposing in oncology and immune-related diseases. This compound has demonstrated anti-cancer properties in various preclinical and clinical studies for different cancer types, including colorectal cancer, gastric cancer, melanoma, and renal cell carcinoma. oncology-central.comecancer.orgnih.gov

The proposed mechanisms underlying this compound's anti-cancer effects are multifaceted and include blocking histamine receptors on cancer cells and modulating the immune system's response against cancer. oncology-central.comecancer.org Histamine and its receptors are present in tumor cells and the tumor microenvironment, suggesting their involvement in tumor progression. researchgate.net this compound is thought to support the immune system's defenses against cancer. oncology-central.comecancer.org

Studies have investigated the use of this compound as an adjunct to conventional cancer therapies. For instance, research has explored the use of perioperative this compound in patients undergoing surgical resection of colorectal cancer, with some findings suggesting a potential survival benefit. nih.govnih.gov A systematic review indicated that repurposing this compound has the potential to offer a survival benefit by acting as an immunomodulatory agent in patients undergoing curative resection for colorectal cancer. nih.gov

Beyond oncology, this compound has shown potential in other immune-related conditions, such as demonstrating beneficial effects on cell-mediated immunity following burn injury and alleviating damage induced by irradiation in animal models through antioxidation and immunomodulation. nih.gov Research is also exploring its potential in neurodegenerative diseases like Parkinson's, investigating its ability to attenuate amyloid formation. researchgate.net

Despite promising results, further large-scale, well-designed prospective studies are needed to definitively establish the efficacy of this compound in these emerging areas. nih.gov

Novel Combination Therapies

Another promising future direction for this compound research involves exploring its use in novel combination therapies. Given its diverse mechanisms of action, particularly its immunomodulatory effects, this compound is being investigated for its potential to enhance the effectiveness of other therapeutic agents.

For example, the potential for this compound to synergize with existing chemotherapeutics is being explored. nih.gov Preclinical studies have indicated that this compound could enhance the cytotoxic effect of cyclophosphamide in animal models. nih.gov

Research is also investigating combinations of this compound with other drugs for cancer treatment. A study proposed investigating a combination of phospho-valproic acid and this compound for pancreatic cancer prevention. grantome.com Additionally, the potential of combining this compound with metformin and ibuprofen has been explored in breast cancer models, with some findings suggesting a decrease in tumor size and increased survival rate. scientificarchives.com