Rifampicin

Synthetic Routes and Reaction Conditions: Rifampicin is synthesized from rifamycin S. The process involves reacting rifamycin S with 1-amino-4-methylpiperazine in an aprotic dipolar solvent at temperatures ranging from 20°C to 100°C . The reaction is typically carried out in a microreactor to improve efficiency and yield .

Industrial Production Methods: Industrial production of this compound involves a continuous flow synthesis starting from rifamycin S and tert-butylamine. This method includes two reaction steps and one purification step, resulting in a 67% overall yield . The process is designed to reduce the consumption of 1-amino-4-methylpiperazine and improve overall efficiency .

Types of Reactions: Rifampicin undergoes various chemical reactions, including oxidation, reduction, and substitution.

Common Reagents and Conditions:

Oxidation: this compound can be oxidized using mild oxidizing agents to form 3-formylrifamycin SV.

Reduction: The reduction of this compound involves the use of reducing agents like sodium borohydride.

Major Products: The major products formed from these reactions include various derivatives of this compound, such as 3-formylrifamycin SV and its subsequent derivatives .

Antimycobacterial Therapy

Primary Use in Tuberculosis Treatment

Rifampicin is a cornerstone in the treatment of both active and latent tuberculosis. It is typically administered in combination with other antibiotics such as isoniazid, ethambutol, and pyrazinamide. The standard regimen lasts six months and has an effectiveness rate of approximately 83% in eradicating the infection caused by Mycobacterium tuberculosis .

Table 1: Standard Tuberculosis Treatment Regimen

Neuroprotective Effects

Recent studies have highlighted this compound's potential neuroprotective properties, particularly in models of neurodegenerative diseases such as Alzheimer’s disease. Research indicates that this compound can inhibit the formation of amyloid-β oligomers and tau hyperphosphorylation, which are critical factors in Alzheimer's pathology .

Case Study: Neuroprotection in Alzheimer’s Models

In a study involving APP OSK mice (a model for Alzheimer's), oral administration of this compound significantly reduced amyloid-β accumulation and improved cognitive functions. Mice treated with this compound showed decreased microglial activation and synapse loss compared to untreated controls .

Treatment of Other Infections

Beyond tuberculosis, this compound is effective against a variety of bacterial infections. It is used to eliminate asymptomatic carriers of Neisseria meningitidis and as prophylaxis for high-risk groups . Additionally, it plays a crucial role in managing prosthetic joint infections due to its efficacy against staphylococcal bacteria .

Table 2: Applications Beyond Tuberculosis

Pharmacokinetic Interactions

This compound is known to induce cytochrome P450 enzymes, which can alter the pharmacokinetics of co-administered drugs. For instance, in studies involving osimertinib (an epidermal growth factor receptor inhibitor), this compound significantly reduced its plasma concentrations when administered concurrently . This interaction underscores the importance of monitoring drug levels when this compound is part of a therapeutic regimen.

Drug Delivery Systems

Innovative research has explored the use of lipid-based nanoparticles for delivering this compound more effectively to target sites, particularly in cancer therapy. These systems enhance the drug's bioavailability and therapeutic efficacy while minimizing side effects .

Rifampicin exerts its effects by inhibiting bacterial RNA synthesis. It binds to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription . This inhibition prevents the bacteria from synthesizing essential proteins, leading to their death . The molecular targets include the bacterial RNA polymerase, and the pathways involved are primarily related to RNA synthesis and protein production .

Comparative Analysis with Structural Analogs

Antimicrobial Efficacy

Rifampicin is compared primarily with rifapentine and rifabutin, which share a similar ansamycin core but differ in side chains, affecting potency, pharmacokinetics, and resistance profiles.

Table 1: In Vitro Antimicrobial Activity Against Mycobacterium tuberculosis

• Rifapentine : In a clinical trial, rifapentine achieved a 95.7% treatment success rate in pulmonary TB, compared to 78.3% for this compound, with a lower relapse rate .
• Cross-Resistance : High-level this compound resistance (MIC ≥32 mg/L) confers resistance to rifapentine and rifabutin, though rifabutin MICs are marginally lower .

Pharmacokinetics and Drug Interactions

Table 2: Pharmacokinetic and DDI Profiles

• PXR Activation : this compound strongly induces CYP3A4, CYP2B6, and ABCB1, whereas structural analogs like compound 25 (a this compound derivative) show 50% weaker induction .
• Rosuvastatin Interaction : this compound reduces rosuvastatin AUC by 50% via OATP1B1/1B3 inhibition, while rifapentine’s impact remains understudied .

Resistance Mechanisms

This compound resistance primarily arises from mutations in the rpoB gene (e.g., S531L). Cross-resistance is prevalent:

• 98% of this compound-resistant M. tuberculosis isolates are resistant to rifapentine and rifabutin .
• Molecular diagnostics like GeneXpert MTB/RIF and line probe assays (LPAs) detect rpoB mutations with 100% concordance in resistance profiling .

Basic Research Questions

Q. What are the standard methodologies for detecting rifampicin resistance in Mycobacterium tuberculosis?

The Xpert® MTB/RIF assay is a widely validated molecular test for simultaneous TB diagnosis and this compound resistance detection. It employs real-time PCR to amplify the rpoB gene and identify mutations linked to resistance. Sensitivity ranges from 88% (as an initial test) to 67% (as an add-on after negative microscopy), with specificity >98% . Culture-based drug susceptibility testing (DST) remains the gold standard but requires weeks for results. For epidemiological studies, resistance trends can be analyzed using χ2 trend tests and spatial mapping tools like GeoDa to visualize regional patterns .

Q. How is this compound content quantified in pharmaceutical formulations?

Near-infrared (NIR) diffuse reflectance spectroscopy is a rapid, non-destructive method. Researchers develop calibration models by correlating spectral data with HPLC-validated this compound concentrations. Key steps include spectral preprocessing (e.g., Savitzky-Golay smoothing), partial least squares regression for model construction, and validation using root mean squared error (RMSE) metrics .

Q. What frameworks guide the formulation of research questions in this compound studies?

The PICOT framework (Population, Intervention, Comparison, Outcome, Time) is effective. For example:

• Population: Adults with this compound-resistant TB in high-burden regions.
• Intervention: Novel this compound-nanoparticle delivery.
• Comparison: Standard oral this compound.
• Outcome: Reduction in treatment duration.
• Time: 6-month follow-up. This structure ensures alignment with gaps in pharmacokinetics or resistance mechanisms .

Q. How are in vitro CYP induction studies standardized using this compound?

this compound serves as a positive control in CYP3A4 induction assays. Data normalization involves expressing test compound fold-induction as a percentage of this compound’s maximal response (e.g., Emax). Curve-fitting models (e.g., sigmoidal dose-response) calculate EC50 values. Compliance with this compound pretreatment protocols is critical to avoid skewed results due to auto-induction variability .

Advanced Research Questions

Q. What experimental designs optimize pH-responsive this compound delivery systems?

A 2⁴ factorial design can evaluate variables like adsorbent mass, pH, and drug concentration. For example, palygorskite clay nanocarriers achieved 33.62 mg/g drug loading at pH 2. Post-synthesis, kinetic models (e.g., pseudo-second-order) and isotherms (e.g., Langmuir) elucidate adsorption mechanisms. Characterization via FTIR, XRD, and SEM confirms drug-clay interactions and amorphous state stabilization .

Q. How can Box-Behnken designs improve this compound nanoparticle formulations?

Box-Behnken response surface methodology (3 factors, 3 levels) optimizes variables like lecithin-oleic acid concentration (X1), this compound dose (X2), and polysorbate 80 (X3). Responses include particle size (Y1) and entrapment efficiency (Y2). Minitab-generated polynomial equations identify significant interactions, e.g., reducing particle size by balancing surfactant and drug ratios .

Q. What bioinformatics tools analyze this compound’s transcriptional effects in bacteria?

The R package rifi processes RNA-seq or microarray time-series data from this compound-treated cultures. Steps include:

• Normalization of intensity values.
• Segmentation to identify transcriptionally active regions.
• Statistical testing for pause sites or internal transcription start sites (iTSS). Outputs reveal this compound’s impact on RNA polymerase dynamics .

Q. How do researchers resolve contradictions in this compound’s CYP induction data?

Discrepancies arise from variability in cell lines (e.g., hepatocytes vs. transfected cells) and this compound exposure protocols. Meta-analyses should stratify data by experimental conditions. Sensitivity analyses exclude outliers (e.g., subjects with 100-fold higher this compound concentrations due to non-compliance) .

Q. What spatial-temporal methods track this compound resistance epidemiology?

GeoDa software maps resistance rates using Moran’s I for spatial autocorrelation. Temporal trends are assessed via χ2 trend tests in SPSS. For instance, Zhejiang Province (2015–2019) reported 5.9% this compound resistance, with hotspots linked to urbanization and healthcare worker exposure .

Q. How are phase 1 trials designed for inhalable this compound formulations?

Dry powder inhalers require particle size optimization (<5 µm for alveolar deposition). Phase 1 trials assess pharmacokinetics (Cmax, AUC) and safety via spirometry and bronchoalveolar lavage. Recruitment criteria exclude patients with chronic respiratory conditions. Data are analyzed using non-compartmental models in Phoenix WinNonlin .