Future Journal of Pharmaceutical Sciences最新文献

Background

Bivalirudin is the preferred anticoagulant for pediatric ventricular assist device (VAD) patients. The manufacturer only permits the diluted drug to be used for 24 h once mixed with the sterile solutions. Most infants on VAD require much less than a single infusion bag in 24 h and any remaining infusion at 24 h must be discarded, resulting in increased medication waste and health care costs. The objective of this study was to examine the effect of storage containers and temperature on the stability and activity of intravenous (IV) bivalirudin solutions.

Results

Diluted bivalirudin (AngioMax®) IV solutions (1 and 5 mg/mL in dextrose 5% in water) were prepared in bags and syringes and stored at room temperature and at 2–8 °C. Bivalirudin concentrations were determined at different time points. Bivalirudin activity was determined by assessing its anticoagulating effect on human plasma via partial thromboplastin time (PTT) prolongation. Results suggest that a compounded bivalirudin infusion solution maintains its therapeutic activity and stability at room temperature for up to 48 h.

Conclusions

Data suggest that bivalirudin solutions in dextrose 5% in water and protected from light are potentially stable at room temperature for up to 48 h. Further studies are needed to confirm our study findings.

Background

Disturbed intestinal integrity and increased permeability are linked to dysbiosis. This disruption involves GIT-related and unrelated diseases, such as neurological diseases. Intake of a high-fat diet (HFD) leads to an imbalance of gut microbiota and regression of bacteria producing “short-chain fatty acids (SCFAs)”. These SCFAs can modulate brain functions. Therefore, we investigated the therapeutic effect of Clostridium Butyricum (CB) bacteria extracted from human faeces on intestinal and neurological impairments induced by HFD and explored their modulation of tight junction protein expression.

Materials and methods

Twenty-four adult male rats were classified into the control group, which received regular rat chow; the HFD group, which received HFD for 16 weeks; and the HFD-Microbiota group, which received HFD as in group II for 16 weeks, but from week 9 received CB (dose of 2 ml (2.3 × 10¹¹ cfu/ml) daily till scarification.

Results

The microbiota improved working memory, episodic-like memory, and emotional memory. Also, there was a substantial decline in the animals’ body weights, serum lipopolysaccharides, interleukin-1β, tumour necrosis factor-α, insulin, glucose, and HOMA index compared to the HFD group. A remarkable increase in brain and colonic claudin-5 and occluding expression of its gene in the microbiota-treated group in comparison with the HFD group was reported. SCFAs, intestinal, brain claudin-5, and occludin genes were positively correlated. Also, a positive correlation was found between the F/B ratio and both brain beta-amyloid and Tau proteins.

Conclusion

Repeated intake of CB hindered systemic /neuroinflammation, enhanced the tight junction proteins’ expression in the gut/brain barrier, and improved cognitive functions.

Background

Prostate cancer is one of the prime causes of death in men worldwide; the number of patients has increased every year despite significant efforts and outlay in the research of prostate cancer. Identifying new natural targets for effective prostate cancer treatment remains a major challenge in contemporary research. Natural products may provide an excellent source for drug development against prostate cancer. The DisGeNET and GeneCards databases were used to identify the anti-cancer proteins involved in prostate cancer. Furthermore, the Search Tool for the Retrieval of Interacting Genes/Proteins database was utilized to identify the hub genes. The hub genes were processed using the Gene Expression Profiling Interactive Analysis database to get the difference in transcriptional expression between prostate cancer tissue and normal tissue. The 3D structures of selected targets were acquired from the protein data bank, and molecular docking was carried out. Higher expression of hub genes such as matrix metalloproteinase-9 (MMP9) was significantly linked with overall and progression-free survival in prostate cancer patients. Finally, the 200 ns molecular dynamics (MD) simulation was performed to check the stable interaction of compounds with the MMP9.

Results

Co-expression investigation demonstrates that identified hub genes play a crucial role in prostate cancer and are controlled by many miRNAs. Molecular docking studies demonstrated that D-Galacturonic acid, glycerides, C14-18 showed better docking scores (− 8.0) with targeted MMP9 protein. MD simulation showed a stable interaction of bioactive compounds, such as D-Galacturonic acid, glycerides, C14-18 with the MMP9 protein.

Conclusions

The present study highlights that bioactive compounds could be an effective anti-cancer drug against MMP9 in prostate cancer and can be further validated using different preclinical studies.

Graphical abstract

Background

Oxidative stress, triggered by an imbalance between reactive free radicals and the body’s antioxidant defenses, is linked to numerous health disorders including neurodegenerative ailments, cancer, and cardiovascular diseases. This study evaluates twenty-nine novel antioxidant flavonoids for their potential as therapeutic agents, focusing on drug-likeness, molecular interactions, pharmacokinetics, and electronic properties.

Results

Using SwissADME for drug-likeness analysis, all selected flavonoids met essential criteria. Molecular docking studies with the Keap1 protein identified Compounds 1, 13, and 15 as top performers, achieving MolDock scores of − 110.910, − 110.941, and − 117.329 kcal/mol, respectively, which indicate strong binding affinities. These compounds demonstrated significant interactions with key residues such as ARG-330 and GLU-250, whereas Ascorbic acid and Trolox showed lower scores of − 77.366 and − 101.037 kcal/mol, respectively. Pharmacokinetic predictions suggested high gastrointestinal absorption and blood–brain barrier permeability for the top flavonoids, with bioavailability scores of 0.55, compared to 0.56 for Ascorbic acid and 0.55 for Trolox. In the DFT assessment, HOMO–LUMO energy gaps were found to be 4.460 eV for Compound 1, 4.530 eV for Compound 13, and 4.520 eV for Compound 15, reflecting strong antioxidant activity. Additionally, electrophilicity indices ranged from − 3.993 to − 4.072, indicating significant electron-donating potential. QSAR analysis highlighted differences in dipole moments, hydrophobicities, and polar surface areas among the compounds, suggesting varied therapeutic potential.

Conclusions

This study highlights the promising potential of novel flavonoids as effective antioxidant agents. Evaluations of their drug-likeness, molecular interactions, and pharmacokinetic properties indicate a favorable profile for therapeutic applications. High binding affinities in molecular docking with the Keap1 protein suggest these flavonoids can modulate oxidative stress pathways, offering protection against various health disorders. Pharmacokinetic predictions show high gastrointestinal absorption and blood–brain barrier permeability, ensuring these compounds reach their target sites effectively. The use of advanced computational methods, such as DFT and QSAR analysis, enhances understanding of their properties and mechanisms. Overall, these findings support the development of effective antioxidant therapies for oxidative stress-related conditions.

Delayed wound healing is a challenge, especially in patients with diabetes mellitus. Red yeast rice (RYR) is a traditional medicine with known uses in several ailments including stasis of blood and weakness of limbs. Experimentally, it was shown to exhibit antidiabetic and anti-inflammatory activities. This study aimed to evaluate the potential of RYR to promote healing of excised skin in diabetic rats. Our data indicated that application RYR in a hydroxypropyl methylcellulose-based gel (5 or 10%) significantly expedited wound retraction. This was associated by significant antioxidant activities of RYR as evidenced by decreased accumulation of malondialdehyde, and enhanced superoxide dismutase and catalase activities in skin tissues. Further, RYR significantly decreased the immune expression of nuclear factor kappa B (NF-κB) and tumor necrosis factor-α (TNF-α). RYR enriched skin content of hydroxyproline and up-regulated mRNA expression of COL 1A1. Also, RYR-treated rats showed higher expression of platelet-derived growth factor B (PDGF-B), vascular endothelial growth factor A (VEGF-A) and transforming growth factor-beta (TGF-β) as compared to untreated control rats. In conclusion, RYR expedites wound healing of diabetic rats. This is at least in part, due to its ability to act as an antioxidant, reduce inflammation, promote collagen production, and support the formation of new blood vessels.

Background

Zingiber officinale rhizomes (Ginger, Zingiberaceae) are used traditionally in treating various ailments, including neurodegenerative diseases. Therefore, its constituents like 6-paradol may be useful in the management of Parkinson's disease (PD). Moreover, promising molecular docking scores of 6-paradol targeting PARKIN1, cAMP-response-element binding protein (CREB), PTEN-induced kinase 1 (PINK1), and tyrosine kinase B (TrKB) proteins associated with PD prompted in vivo investigations to assess its therapeutic potential on rotenone-induced PD in rats.

Results

6-Paradol-treated rats showed improved muscular coordination in grip-strength, rotarod, and open-field tests and reduced histopathological damage. 6-Paradol increased tyrosine hydroxylase immunoreactivity and rescued dopaminergic neurons in the nigrostriatal pathway. It suppressed neuroinflammation by downregulating high-mobility group box 1 (HMGB-1) and Toll-like receptor 4 (TLR4) mRNA expressions and decreasing nuclear factor kappa-B (pS536-NFκB) p65 and tumor necrosis factor-alpha (TNF-α) protein levels. Additionally, 6-paradol inhibited necroptosis by reducing TNFR1 gene expression and RIPK1, RIPK3, and MLKL protein contents. It also enhanced mitochondrial biogenesis, increasing mitochondrial transcription factor-A (TFAM) peroxisome proliferative-activated receptor-gamma (PPARγ), and PPARγ coactivator 1 alpha (PGC-1α) protein levels, thereby reducing malondialdehyde and increasing glutathione levels. These effects of 6-paradol were comparable to L-dopa/carbidopa.

Conclusion

The neuroprotection potential of 6-paradol is related to suppression of neuroinflammation, inhibition of necroptosis, enhancement of mitochondrial biogenesis, and alleviation of oxidative stress. These findings further supported the traditional uses of ginger for neurodegenerative disorders.

Graphical abstract

Background

The bacterial resistance is an increasing obstacle against the global health that necessitates innovation of new approaches. Targeting bacterial resistance is one of the promising approaches. Pseudomonas aeruginosa is a clinically significant opportunistic pathogen and causes wide diverse of illness. The P. aeruginosa virulence is regulated by several systems as quorum sensing (QS) systems. Additionally, P. aeruginosa could employ membranal sensors to sense the neurotransmitters enhancing the virulence. Fluoxetine (FLU), an antidepressant, functions by inhibiting the reuptake of the neurotransmitter serotonin. This study aimed to assess the anti-virulence activity of FLU against P. aeruginosa. The effect of FLU at sub-inhibitory concentration was evaluated on the biofilm formation, removal of preformed biofilms, production of virulence factors such as protease, hemolysins, elastase, rhamnolipids, motility, pyocyanin, and pyoverdine. The impact of FLU on the expression of virulence-related genes was estimated. An invasion assay and mice protection assay were conducted to assess the FLU’s diminishing effect on P. aeruginosa pathogenesis.

Results

The results showed significant ability of FLU to inhibit the biofilm formation, bacterial motility, and production of virulence factors. These antibiofilm and anti-virulence activities of FLU were owed to the downregulation of genes involved in expression of QS systems and bacterial espionage. FLU significantly lowered the bacterial invasion and protected mice from P. aeruginosa. Additionally, synergistic outcome was obtained when FLU was combined with antibiotics.

Conclusion

FLU exhibits potent antibiofilm and anti-virulence effects at sub-MIC levels, likely mediated by its inhibition of QS systems. These results position FLU as a promising candidate for adjuvant therapy against drug-resistant P. aeruginosa infections.

Background

Diabetic patients are at a significantly higher risk of delayed and impaired wound healing, with increased susceptibility to wound infections and dehiscence. The pathophysiology of abnormal wound healing in diabetes is multifactorial, involving impaired vascularization, reduced cellular proliferation, and prolonged inflammation, all associated with hyperglycemia. This randomized controlled trial (ClinicalTrials.gov registration: NCT06400082) included 74 type 2 diabetic patients undergoing elective abdominal surgeries with wound lengths ≥ 10 cm. Patients were randomized into two equal groups to receive either topical saline dressings or topical regular insulin. Wound dressing and assessments were performed daily until complete closure. Outcomes included percentage reduction in wound surface area, healing days, and unit healing time (UHT). Skin sections were collected on days 0 and 7 to evaluate e-cadherin, Ki67, IL-6, 8-hydroxy-2’-deoxyguanosine (8-OHdG), and histological architecture.

Results

Topical insulin significantly enhanced wound healing outcomes, demonstrating a greater percentage reduction in wound surface area (p < 0.001) and a lower UHT at day 7 in the insulin group (4450.00 [3000.00–5460.00]) compared to the saline group (2594.00 [2090.00–7560.00]), p = 0.001). Insulin-treated wounds exhibited increased tissue expression of collagen, e-cadherin, and Ki67, along with significantly reduced levels of IL-6 and 8-OHdG (p < 0.05).

Conclusion

Topical insulin is a promising therapeutic strategy for improving postoperative wound healing in diabetic patients. It enhances tissue repair by modulating inflammation, oxidative stress, and cellular proliferation.

Background

The liver is a vital organ that detoxifies drugs and xenobiotics. However, breaking down toxins creates byproducts that can damage the liver. Silibinin possesses a proven hepatoprotective and antioxidant effect as it inhibits the free radicals produced from the metabolism of toxic substances, such as paracetamol and ethanol. Unfortunately, the poor bioavailability of silibinin hinders its use, which could be overcome by loading it into lipid nanocarriers, such as cubosomes. This study aims to formulate silibinin-loaded cubosomes and evaluate their hepatoprotective effect in vivo.

Results

A full factorial design was conducted to evaluate the percentage of poloxamer 407 and the sonication time. The prepared cubosomes were characterized by multiple characterization techniques. The in vitro release of silibinin from the chosen formulation was also evaluated. An induced acute paracetamol hepatotoxicity model in mice was utilized for in vivo evaluation. The particle size of the formulated cubosomes ranged from 123.2 to 210.9 nm, and the polydispersity index range was 0.226–0.560. The zeta potential of the formulations ranged between − 14.2 and − 25.6 mV. The chosen formulation displayed a controlled release pattern. The chosen formulation showed a significant hepatoprotective action by reducing the liver marker enzymes. The histopathological study also confirmed the hepatoprotective activity of the chosen cubosomes. The hepatoprotective effects of the chosen formulation can be attributed to positive impacts on oxidative stress, as demonstrated in oxidative stress markers.

Conclusion

The obtained results suggest that silibinin-loaded cubosomal formulation offers apotentially improved hepatoprotection effect against induced acute paracetamol hepatotoxicity.

Graphical abstract

Background

A bioanalytical method was developed and validated in accordance with US FDA guidelines for estimating Imeglimin hydrochloride levels in human plasma using liquid chromatography with mass spectrometry (LC–MS/MS). Imeglimin, an oral antidiabetic medication, has demonstrated significant efficacy in reducing high blood sugar levels in individuals with type 2 diabetes, including both Japanese and Caucasian populations.

Results

The method demonstrated excellent linearity with correlation coefficients (r²) exceeding 0.99 across six calibration curves. Calibration standards showed accuracy within the US FDA’s acceptable range of 99.28–101.09%, and precision varied from 1.10 to 10.19%. Recovery assessment revealed a mean recovery of 76.59% for the internal standard and 85.48% accuracy for the dilution quality control. Stability studies under various conditions, including benchtop, dry extract, wet extract, freeze–thaw, and long term, confirmed the high stability of both the drug and the internal standard, with stability percentages within acceptable limits. The environmental impact assessment utilizing the green analytical procedure index resulted in a score of 0.1, indicating minimal environmental impact, while the analytical greenness metric approach yielded a score of 0.85, indicating efficient resource utilization.

Conclusion

The validated LC–MS/MS method demonstrates strong linearity, accuracy, and precision, along with high stability under various conditions. Its minimal environmental impact and efficient resource utilization make it suitable for the routine analysis of Imeglimin hydrochloride levels in human plasma.

Graphical abstract