Future Journal of Pharmaceutical Sciences最新文献

Background

Understanding how a disease develops and the factors that influence any deviation from the balance created by the body is critical in tailoring appropriate treatment for each patient. Existing literature discusses each factor separately, and simply touches on the interaction by recognizing its existence. The objective of this study is to delve in to the relationship between the immune system and the gut microbiota, and how they in turn affect each other and ultimately lead to a diseased state.

Methods

To locate relevant published research, a comprehensive search of electronic databases was performed. Eligible studies were chosen based on predetermined inclusion criteria, which included original research publications exploring the link between the immune system and gut microbiome in IBD patients. Data extraction and quality evaluation followed the PRISMA recommendations. The included studies used a variety of techniques, including observational cohort studies, case–control studies, and experimental research.

Results

Changes in systems from homeostatic function include a dysregulated immune response with heightened pro-inflammatory cytokines, disrupted gut barrier permeability due to increased epithelial permeability and disrupted tight junctions, reduced microbial diversity with elevated levels of pathogenic strains and bacteriophages. Short-chain fatty acids which promote gut barrier integrity and possess anti-inflammatory effects are reduced in patients with IBD.

Discussion

Key findings from the literature review emphasize the role of gut microbiota in immunological responses in IBD, as well as the reciprocal impact of immune dysregulation on microbiome composition. Further research is needed to understand the molecular interaction between the immune system and the gut microbiota (Caron et al. in J Crohns Colitis 18:ii3–ii15, 2024. https://doi.org/10.1093/ECCO-JCC/JJAE082).

The aryl hydrocarbon receptor (AHR) ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays a pivotal role in modulating various biological processes, including circadian rhythms and maintenance of cellular homeostasis. This study aimed to investigate the pharmacokinetics, tissue distribution, and metabolic clearance of FICZ in vivo using high-performance liquid chromatography (HPLC) with fluorescence detection and an ethoxyresorufin-O-deethylase (EROD) assay. FICZ was administered intraperitoneally to rats in varying doses (42.6 µg/kg, 85.2 µg/kg, 127.9 µg/kg, and 426.4 µg/kg) at multiple time points (1, 3, and 6 h). The liver was identified as the primary organ for FICZ distribution, with peak concentrations observed at 1 h, whereas metabolism by cytochrome P450 enzymes, particularly CYP1A1, led to a significant reduction in FICZ levels over time. Additionally, heart, testis, and brain tissues exhibited varying FICZ accumulation patterns, with dose-dependent distribution observed in testes. The findings highlight the tissue-specific pharmacokinetics of FICZ, with its distribution influenced by both dose and exposure time. EROD activity, a marker for CYP1A1 induction, peaked at 3-h post-administration and was inversely correlated with FICZ degradation. The rapid metabolism of FICZ, exacerbated by its susceptibility to photodegradation, complicates the detection and quantification of endogenous FICZ in vivo. This study presents the first comprehensive assessment of FICZ pharmacokinetics and tissue distribution in various rat tissues, including the liver, heart, brain, prostate, and testis, while also exploring its link to CYP1A1 modulation. This study underscores the complexity of FICZ’s pharmacokinetic, suggesting that both dose- and tissue-specific responses play crucial roles in AHR activation and subsequent enzyme activity. These results contribute to a deeper understanding of FICZ’s biological effects, offering insights into its therapeutic potential and toxicological implication.

Background

The present work aims to develop and validate an LC–MS/MS method for the bioanalysis of a fixed-dose combination containing 325 mg of paracetamol and 50 mg of camylofin in human serum.

Results

A selective, sensitive and fast LC–MS/MS method was developed and validated for quantitative bioanalysis of the analytes from human serum, using protein precipitation technique and diphenylamine as an internal standard (IS). Chromatographic separation was performed on Agilent Zorbax SB C18 column (50 mm × 2.1 mm, 5 μm), using a mixture of 0.1% formic acid and methanol (50: 50 v/v) as mobile phase at a flow rate of 0.5 mL/min, with a run time of 6 min. Tandem mass spectrometry (MS/MS) was employed for the analysis, utilising positive ionisation mode and a multiple reaction monitoring (MRM) scan type. The method was established with a linear range of 100–20,000 ng/mL for paracetamol and 0.25–200 ng/mL for camylofin using 200 μL of human serum.

Conclusion

The developed bioanalytical method was validated as per the Bioanalytical Method Validation Guidance for Industry of the United States Food and Drug Administration (US-FDA)-CDER. The developed method is reliable and easy to use and was applied successfully to a clinical pharmacokinetic study involving twelve healthy Indian subjects under fasting and fed conditions.

Purpose

Patients on regular hemodialysis (HD) are at the highest risk of developing anemia. Vitamin D deficiency is more prevalent in HD patients. Recent studies have suggested that improving vitamin D status can reduce both anemia and the need for higher recombinant human erythropoietin (EPO) dosing. This study is to demonstrate the pleiotropic effects of two regimens of cholecalciferol intake on the hemoglobin (Hgb) levels, ferritin levels, transferrin saturation (TSAT), total iron-binding capacity (TIBC) and the erythropoietin sensitivity index (ERI) in HD patients.

Methods

A prospective, randomized, single blinded trial was conducted to evaluate the effect of weekly versus monthly cholecalciferol administration on anemia parameters and erythropoietin sensitivity in hemodialysis (HD) patients. Fifty eligible patients undergoing HD were randomly allocated to receive either weekly doses of 50,000 IU or monthly doses of 200,000 IU cholecalciferol. Various parameters including Hgb levels, ferritin levels, TSAT, TIBC, ERI, and cumulative dose of erythropoietin (EPO) were evaluated both at baseline and at endpoint. This study was registered at Clinicaltrial.gov, identifier number (NCT05922696), registered 2023/06/20 (Retrospectively registered).

Results

Adding weekly or monthly cholecalciferol to standard HD care for three months resulted in a 72% reduction in EPO doses for thirty-six out of fifty patients. Both regimens significantly increased Hgb levels, with the weekly regimen showing a greater increase (+ 2.67 g/dl vs. + 0.70 g/dl; P < 0.001). The weekly regimen also led to a significant increase in TSAT (P = 0.005) and a decrease in ferritin levels (P = 0.03). Moreover, the weekly regimen significantly reduced EPO doses (−11,600 IU vs. −6,160 IU) and ERI (−4.76 vs. −2.68; P < 0.001) compared to the monthly regimen.

Conclusion

Cholecalciferol demonstrated a beneficial impact on anemia in HD patients. Weekly 50,000 IU regimen had better control over Hgb, TSAT, TIBC, EPO dosing, and erythropoietin sensitivity compared to the monthly 200,000IU regimen.

ClinicalTrials.gov registration number: NCT05922696.

Antimicrobial resistance remains a major global public health challenge, contributing to increased mortality rate and treatment failures in an effort to address this growing challenge, the present research work focused on the synthesis and evaluation of new hydrazone scaffold and pyrazoline derivatives (coded HS6–HS10) as potential antimicrobial agents. The target compounds were synthesized via one-pot condensation reactions and characterized using FTIR, ¹H, and ¹³C NMR techniques. Their antimicrobial activities were assessed in vitro against a panel of Gram-positive, Gram-negative bacteria, and fungal strains.  However, their assessment revealed broad spectrum of antimicrobial activity, where the compounds bearing biaryl-substituted hydrazones with electron-donating or electron-withdrawing groups at para- and or meta-positions showed highest potency. However, MIC values of 12.5 mg/mL were observed against clinical isolates such as E. coli, S. typhi, and P. aeruginosa, while S. aureus, B. subtilis, and S. pneumoniae were inhibited at 12.5–25 mg/mL, while MIC values of 50 mg/mL were recorded against Aspergillus niger, indicating weak antifungal activity. The molecular docking studies conducted using target microbial enzymes such as dihydrofolate reductase (DHFR) and squalene epoxidase (SQLE) against the ligands HS7 and HS8 have strong binding affinities towards DHFR (− 9.6 and − 9.4 kcal/mol) and SQLE (− 9.8 and − 10.2 kcal/mol), respectively, outperforming standard reference drugs ciprofloxacin (− 7.4 kcal/mol) and terbinafine (− 9.8 kcal/mol). Meanwhile, the in silico ADME analysis confirmed that all compounds satisfied Lipinski’s rule of five, suggesting favourable drug-like properties. In conclusion, these findings suggest that substituted hydrazone and pyrazoline derivatives possess considerable promising scaffolds for developing better novel antimicrobial agents that are capable of combating resistant pathogens.

Background

Quality by design (QbD) adverts toward gaining of few expected quality with predetermined and desired specifications. Analytical quality by design (AQbD) approach toward the development of analytical method can significantly lead toward the rugged and robust method specially the assessment and risk management compared to traditional approaches. The aim of present study is to develop an analytical method for the estimation of Picroside II in bulk and pharmaceutical dosage form through RP-HPLC assisted by AQbD.

Result

The important critical parameters were methodically optimized by the experimental design space of Box–Behnken, and model graphs were plotted by utilizing Design Expert Software trial version 13.0. The Picroside II separation was successfully done on the HPLC system of Waters equipped through UV-Visible detector on Waters X Bridge RP C18 column having dimensions (4.6 mm × 150 mm, 5.0 μm), mobile phase containing 0.1% formic acid and acetonitrile (77:23%v/v), and rate of flow at 1.0 mL/min. The wavelength for detection was 266 nm; retention time of Picroside II was between 6.0 and 6.2 min with a total duration run time of 10 min. The proposed developed technique was found to be specific, precise (% RSD < 2%), linear (6–14 μg/mL), and robust (% RSD < 1%). Additionally, forced degradation studies were established and the % drug assay was found to be 99.46 ± 0.86% including the results of specificity in terms of peak purity suggesting no interference of any unidentified peak with the chromatographic peak of Picroside II. The results of all the method validation parameters were within the recommended limit of ICH Q2(R1) guidelines. The proposed method was proved to be green as performed by green assessment tools.

Conclusion

The AQbD-based developed method helped in the design and operating space generating with the knowledge of all the method validation characteristics, and the developed RP-HPLC method on the AQbD-based approach was very useful for Picroside II estimation in bulk and pharmaceutical dosage forms.

Background

Attention-deficit hyperactivity disorder (ADHD) is a state of poor attention and hyperactivity. Neuroinflammation and oxidative stress are complicated in the pathology of ADHD. Betanin is a potent water-soluble nitrogen-containing antioxidant and anti-inflammatory molecule not tested before in ADHD models. The current study aimed to test the ability of betanin to mitigate ADHD in mice in terms of cognitive and motor dysfunction, in addition to brain histopathology, neurotransmitter levels and inflammatory protein levels; the molecular study was supported by a bioinformatic investigation. Male albino mice were allotted to three experimental groups: (i): normal, (ii): ADHD group, (iii) ADHD + betanin 50 mg/kg. We induced ADHD by including monosodium glutamate (SGLU) in the diet for 8 weeks. Cognitive and motor dysfunction were evaluated using the open field test (OF-T) for locomotor alterations, the marble burying test (MB-T) for attention and compulsive behavior, and the rope crawling test.

Results

The ADHD control group (fed with SGLU) showed increased activities in the OF-T and high compulsive behavior in the MB-T. Further, high brain glutamate and low dopamine levels were observed in the ADHD control group along with high levels of malondialdehyde and inflammatory parameters such as toll-like receptors (TLRs), tumor necrosis factor-α (TNF-α), nuclear transcription factor-κB (NFκB), interleukin-1β (IL-1β), and IL6. Conversely, brain Nrf2 and total antioxidants were reduced in the ADHD group. Microscopic investigation showed pathological alterations in the brain. Western blot analysis and immunostaining showed greater levels of p-53 in the ADHD group versus the normal group.

Conclusions

Orally administered betanin improved most neurobehavioral, biochemical, and histopathological findings in the ADHD model in mice. Hence, betanin can be considered for further investigation as a useful food component in children for mitigating ADHD symptoms.

Graphical abstract

The present research work is an application of Quality-based Design (QbD) approach for the development of sensitive and selective stability indicating chromatographic methods for the simultaneous estimation of AXS-05 in its synthetic mixture. The combination is in the clinical trial, so the complete work was performed in the synthetic mixture. Fractional factorial design was used to optimize the chromatographic conditions for HPLC method for the synthetic mixture. The optimized method for the combination produced sharp peaks with good resolution (> 2). Method development for the combination is validated by RP-HPLC (QbD approach). Accuracy, precision, linearity, LOD, LOQ, repeatability, reproducibility and percentage recovery are complied with ICH guidelines. Forced degradation study for the synthetic mixture of the combination is performed. Synthetic mixture was treated for acid hydrolysis, base hydrolysis, oxidative stress and thermal stress. Percentage degradation obtained was within the limit, and all the results were complied with ICH guideline. The proposed method is found to be simple, sensitive, economical, precise and robust and can be applicable to the routine analysis of the selected combination.

Background

In the current study, various S-naproxen derivatives (NDs) were evaluated for their analgesic and anti-inflammatory activities using in vivo models, along with molecular docking studies. The analgesic potential was assessed through acetic acid-induced writhing, hot plate, and formalin-induced jumping tests. Anti-inflammatory effect was investigated using carrageenan-induced paw edema model. An acute toxicity study was also conducted to ensure safety.

Results

All tested NDs in different doses were found to be safe in the acute toxicity study. In the acetic acid-induced pain model, NDs (5 mg/kg) showed a significant (p < 0.001) analgesic effect with compound 3 and 7 demonstrated maximum effect (80%). In hot plate test, compounds 7, 8, and 9 showed central analgesic activity with percent effects of 61, 48 and 45%, respectively (p < 0.05). In formalin-induced pain model, all NDs demonstrated significant analgesic activity (p < 0.001), with a stronger effect in the second phase of the test. For anti-inflammatory activity, NDs showed variable effects, with compound 7 (81.55%) and compound 8 (80.14%) showing the highest activity in the third hour of the carrageenan-induced paw edema model. Molecular docking studies confirmed strong interactions of NDs with both opioid receptors and COX-II enzymes, supporting their peripheral and central analgesic mechanisms.

Conclusion

The findings suggest that the tested S-naproxen derivatives exhibit significant analgesic and anti-inflammatory activities. The combination of in vivo and in silico data supports the analgesic and anti- inflammatory effects.

Neurodevelopmental disorders (NDDs) significantly affect brain development, leading to challenges in communication, learning, and emotional regulation. This review examines the role of genetic factors, particularly copy number variations (CNVs), and critical structural alterations in the genome that influence gene dosage and biological functions. We focus on key CNV regions, including 16p11.2, 22q11.2, 1q21.1, and 15q11.2, associated with various NDDs and their impact on cognitive and behavioral outcomes. CNVs can disrupt gene function, contributing to genetic instability and dysregulated pathways in NDDs. Acknowledging limitations in current literature, such as sample size and selection bias, we emphasize the need for a larger, more diverse population and longitudinal studies. Additionally, we identify gaps in understanding genetic-environmental interactions and suggest that advanced genomic technologies could enhance research. Understanding how CNVs influence DNA repair mechanisms may lead to potential interventions to mitigate genomic instability in NDDs.

Graphical abstract