Cimetidine

Synthetic Routes and Reaction Conditions: Cimetidine can be synthesized through various methods. One common method involves converting (5-methyl-1H-imidazole-4-yl) methanol into nitrate ester, which then reacts with N-cyano-N’-methyl-N’-mercaptoethylguanidine ether to produce this compound . Another method involves condensing 2-(4-methylimidazol-4-yl) methylthioethylamine hydrochloride with carbon disulfide in the presence of a base and a desulfurization reagent to form an intermediate, which is then reacted with monomethylamine and cyanamide to yield this compound .

Industrial Production Methods: Industrial production of this compound often focuses on optimizing yield and minimizing environmental impact. For example, some methods avoid generating volatile methyl mercaptan, which is harmful to the environment .

Types of Reactions: Cimetidine undergoes various chemical reactions, including oxidation, reduction, and substitution. It is known to inhibit many isoenzymes of the hepatic cytochrome P450 enzyme system .

Common Reagents and Conditions: Common reagents used in the synthesis of this compound include nitrate esters, carbon disulfide, monomethylamine, and cyanamide . Reaction conditions typically involve mild temperatures and the presence of desulfurization reagents to ensure high yield and minimal byproducts .

Major Products Formed: The major products formed from the reactions involving this compound include this compound sulfoxide and hydroxythis compound .

Cimetidine has a wide range of scientific research applications. In medicine, it is used to manage conditions like GERD, peptic ulcer disease, and indigestion . It also has potential anticancer activity by interfering with histamine-mediated immunomodulation . In chemistry, this compound is used to study reaction kinetics and photochemistry . Additionally, it has been explored for its antiandrogenic properties in treating conditions like hirsutism and androgenetic alopecia .

Cimetidine exerts its effects by competitively inhibiting the action of histamine at the histamine H2 receptors on the basolateral membrane of gastric parietal cells . This inhibition reduces gastric acid secretion, gastric volume, and acidity . This compound also blocks the activity of cytochrome P450 enzymes, which may explain its use in neoadjuvant therapy .

Cimetidine is often compared with other H2 receptor antagonists like ranitidine and proton pump inhibitors like omeprazole and pantoprazole . While all these compounds reduce gastric acid secretion, this compound is unique in its ability to inhibit cytochrome P450 enzymes . This property makes it distinct from other similar compounds, which may have fewer drug interactions and adverse effects .

• Ranitidine
• Omeprazole
• Pantoprazole
• Famotidine

Cimetidine, a histamine H2-receptor antagonist, has been widely used for the treatment of peptic ulcers and gastroesophageal reflux disease. However, recent research has uncovered its diverse biological activities beyond acid suppression, particularly in immunomodulation and potential anti-cancer effects. This article explores the biological activity of this compound, supported by data tables, case studies, and detailed research findings.

This compound primarily functions by inhibiting the action of histamine at H2 receptors located in the gastric mucosa. This inhibition reduces gastric acid secretion, leading to therapeutic effects in acid-related disorders . However, its biological activity extends into the modulation of immune responses and interactions with various cellular pathways.

Immunomodulatory Effects

Recent studies have highlighted this compound's role as an immunomodulatory agent. It has been shown to enhance T cell populations (CD3+, CD4+, and CD8+) and M1 macrophages in tumor microenvironments, which may augment immune responses against tumors . This is particularly significant in cancer therapy, where this compound has been observed to interact with immune checkpoint inhibitors like anti-PD-1 and anti-PD-L1.

Case Study: this compound in Colon Cancer

A study investigating this compound's effects on colon cancer demonstrated that it could reverse the decrease in circulating and tumor-associated neutrophils induced by anti-PD-L1 therapy. This suggests that this compound may reduce the sensitivity of certain tumors to immunotherapies . The findings indicate that while this compound can enhance immune cell populations, it may also attenuate the effectiveness of some cancer treatments.

Table 1: Summary of this compound's Biological Activities

Clinical Implications

This compound's ability to modulate immune responses has led to its exploration as an adjunct therapy in cancer treatment. Clinical studies suggest that it may improve outcomes when used alongside traditional chemotherapeutics. For example, this compound has been shown to increase the plasma concentration of drugs like epirubicin, potentially enhancing their efficacy .

Research Findings

In a comprehensive review of pre-clinical and clinical data, this compound was found to exhibit anti-cancer properties across various models. The mechanisms proposed include:

• Histamine Modulation : Altering histamine levels can influence tumor growth dynamics.
• Immune System Activation : Enhancing T cell activity and macrophage function can lead to improved anti-tumor responses.
• Synergistic Effects with Chemotherapy : this compound may potentiate the effects of certain chemotherapeutic agents .

Safety and Side Effects

While this compound is generally well-tolerated, its immunomodulatory effects necessitate caution in specific patient populations, particularly those undergoing immunotherapy. The potential for altered drug metabolism due to cytochrome P450 inhibition also raises concerns about drug interactions .

Table 2: Reported Side Effects of this compound

Q. What experimental designs are recommended for studying cimetidine’s antiandrogenic effects in preclinical models?

Answer: Preclinical studies on this compound’s antiandrogenic effects (e.g., gynecomastia, prolactin elevation) should employ multi-group designs with dose-dependent administration. For example, a study using pregnant albino rats divided into control and experimental groups (e.g., 5 g/day vs. lower doses) can assess offspring teratogenicity via behavioral tests like the T-maze . Hormonal assays (prolactin, estradiol) and histopathological analysis of mammary tissue are critical. Note that dose selection must account for species-specific metabolic differences and validate results with human cell lines (e.g., androgen receptor binding assays) .

Q. How can contradictory findings on this compound’s antitumor efficacy be reconciled in gastrointestinal cancer research?

Answer: Discrepancies arise from variations in tumor models and molecular targets. For instance, this compound inhibits E-selectin expression in TNF-α-stimulated endothelial cells (IC₅₀: ~42 nM) via RT-PCR and flow cytometry , but shows no effect on cisplatin cytotoxicity in OCT2-high ovarian cancer cells . Researchers should standardize models (e.g., syngeneic vs. xenograft), validate target engagement (e.g., H2 receptor vs. immune modulation), and use transcriptomic profiling to identify context-dependent pathways .

Q. What methodologies are optimal for analyzing this compound’s pharmacokinetic interactions with CYP450 substrates?

Answer: Use in vitro hepatic microsome assays to quantify CYP450 inhibition (e.g., CYP3A4, CYP2D6) and validate with clinical pharmacokinetic studies. For example, this compound prolongs diazepam half-life by 46% via competitive CYP3A4 inhibition . High-performance liquid chromatography (HPLC) with validated standard curves (e.g., linear range: 0.05–10 µg/mL) ensures precise measurement of drug concentrations in plasma . Physiologically based pharmacokinetic (PBPK) modeling further predicts interactions in populations with renal/hepatic impairment .

Q. How should researchers address this compound’s environmental persistence in ecotoxicology studies?

Answer: this compound’s high soil mobility (Koc = 39) and pH-dependent speciation (pKa = 6.8) necessitate studies using HPLC-UV or LC-MS to quantify photodegradation products . Laser flash photolysis identifies reactive moieties (e.g., imidazole ring oxidation by singlet oxygen, k = 3.3 × 10⁶ M⁻¹s⁻¹ at pH 4) . Field studies in river water should correlate degradation rates with dissolved organic carbon and sunlight intensity .

Q. What statistical approaches resolve conflicting data on this compound’s peri-operative benefits in cancer?

Answer: Meta-analyses of randomized trials (e.g., gastric cancer survival studies ) should apply fixed-effects models to account for heterogeneity in dosing (e.g., 800 mg/day vs. 400 mg/day) and outcome measures (e.g., recurrence vs. metastasis). Subgroup analyses stratified by tumor stage (e.g., TNM classification) and adjuvant therapies (e.g., 5-FU) improve specificity. Bayesian methods can weigh evidence from preclinical (e.g., 3LL cell migration assays ) and clinical datasets .

Q. How can researchers optimize solubility studies for this compound in formulation development?

Answer: Use the NRTL-SAC model in Aspen Properties to predict solubility in mixed solvents (e.g., ethanol-water) . Validate experimentally via UV-vis spectrophotometry (low solubility) or HPLC (high sensitivity) against USP reference standards . Report solubility as mean ± SD with one-way ANOVA and Bonferroni correction for multiple comparisons (α = 0.05) .

Q. What protocols mitigate bias in assessing this compound’s reproductive toxicity?

Answer: Follow OECD guidelines for teratogenicity studies, including blinded histopathology reviews and litter-based analysis to control for maternal effects . Measure fetal serum vitamin B12 (linked to long-term H2 blockade ) and use sham-operated controls to distinguish drug effects from surgical stress. Confounding factors like strain-specific susceptibility (e.g., albino rats vs. C57BL/6 mice) must be documented .

Q. How do OCT2 inhibition assays inform this compound’s role in drug-disease interactions?

Answer: Use HEK293 cells transfected with human OCT2 to quantify inhibition constants (e.g., this compound Ki = 15 µM ). In diabetic rat models, compare metformin pharmacokinetics with/without this compound co-administration, analyzing plasma via LC-MS/MS. PBPK models incorporating renal OCT2 expression levels predict clinical relevance .

Q. Basic vs. Advanced Research Focus

• Basic: Mechanisms (H2 receptor antagonism, CYP450 inhibition), standard PK/PD methods.
• Advanced: Tumor microenvironment modulation, environmental fate, systems pharmacology.