Iranian Journal of Pharmaceutical Research最新文献

Background: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and oxidative stress, creating a need for the development of new therapeutic agents. Traditional Chinese medicine (TCM) compounds, such as hainanolidol and norwogonin, have shown potential neuroprotective activity.

Objectives: This study investigates the inhibitory action of these compounds on cholinesterase enzymes and their possible therapeutic application in an AD-like rat model generated by lead acetate (PbAc), a well-known neurotoxicant that mimics AD-associated oxidative damage and cognitive decline.

Methods: The cholinesterase inhibitory activity of nine TCM compounds was assessed in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with donepezil and tacrine as controls. Hainanolidol and norwogonin, identified as the most potent inhibitors, were further evaluated in a PbAc-induced AD rat model to assess their neuroprotective effects. Oxidative stress biomarkers malondialdehyde (MDA), glutathione (GSH), cholinesterase activity, and in silico molecular interactions were analyzed, including docking studies, molecular dynamics (MD) simulations, and ADME-toxicity profiling.

Results: Hainanolidol and norwogonin showed strong nanomolar-range inhibition of both AChE and BuChE, with considerable IC₅₀ values superior to those of standard inhibitors. In the PbAc-induced AD model, both compounds significantly reduced MDA levels and increased GSH levels, indicating oxidative stress mitigation.The level of cholinesterase activity inhibition was as effective as, or more effective than, the suppression achieved by standard treatments, particularly regarding AChE, thus suggesting enhanced therapeutic potential compared to donepezil. Molecular docking and MD simulations confirmed stable binding interactions with key catalytic residues of AChE and BuChE, reinforcing their inhibitory mechanisms. ADME-toxicity analysis further demonstrated favorable pharmacokinetics and safety profiles.

Conclusions: This study concludes that both hainanolidol and norwogonin are worthy of being regarded as dual cholinesterase inhibitors with antioxidant properties, which may serve as alternative therapeutics for AD. The use of PbAc as an AD model underscores the role of environmental neurotoxins in disease pathogenesis, offering insights into novel intervention strategies. Advanced preclinical and clinical studies are needed for further validation.

Background: Cancer is a deadly and multifaceted disease that poses a significant challenge to treatment due to its heterogeneity and ability to adapt and evolve. Despite advancements in research and medicine, the development of effective treatment options remains a major obstacle in the battle against cancer. Manganese oxide (MnO) and iron (III) oxide (Fe₂O₃) nanoparticles (NPs) are increasingly used for numerous new applications in modern industrial sectors. However, the toxic and treatment impact of MnO and Fe₂O₃ NPs has not been clearly elucidated on human cell lines at the cellular and molecular levels.

Objectives: This study aimed to assess the potential cytotoxic effect of combining infrared (IR) laser therapy with MnO and Fe₂O₃ nanoparticles on breast and colorectal cancer cells for cancer treatment.

Methods: We treated the cancer cells with MnO and Fe₂O₃ NPs and then exposed them to IR radiation for 6, 12, 24, 48, and 72 hours to investigate the effectiveness of this cancer treatment approach. To evaluate cytotoxicity, we conducted assessments on Skbr3 and HT29 cancer cells, both individually and in combination, using various methods.

Results: The findings indicate that despite the inherent toxicity of NPs and IR laser radiation on cancer cells, the utilization of MnO and Fe₂O₃ NPs in conjunction with IR laser radiation treatment had the highest cytotoxic impact on cancer cells.

Conclusions: These findings suggest that using MnO and Fe₂O₃ NPs in combination with IR laser therapy has great potential as an effective method for reducing the population of cancer cells.This revision maintains the original content while ensuring clarity and adherence to the AMA style guidelines.

Background: Vancomycin is commonly used in intensive care units (ICUs), but its optimal dosage in patients with acute kidney injury (AKI) remains uncertain. This study aimed to evaluate vancomycin's pharmacokinetic and pharmacodynamic (PK/PD) properties, therapeutic target attainment area under the curve/minimum inhibitory concentration (AUC/MIC ≥ 400) under two dosage regimens, and the need for dosage adjustments in AKI.

Objectives: The primary objective was to assess the proportion of patients achieving a therapeutic AUC/MIC ratio of 400 - 600 mg.h/L and to analyze PK/PD parameters, including volume of distribution (Vd), half-life (T½), and elimination constant (K). The secondary objective was to evaluate kidney function decline, the requirement for renal replacement therapy (RRT), and mortality rates.

Methods: A single-blind randomized clinical trial (IRCT20130917014693N16) was conducted at Loghman Hakim Hospital, Tehran, Iran. Patients over 18 years of age who received at least four doses of vancomycin and developed AKI were included in the study. Eligible patients were randomly allocated into either the intervention or control groups. The intervention group received vancomycin without any dose adjustment, while the control group's vancomycin dose was adjusted based on daily vancomycin clearance, following the standard protocol in our ICU. Daily serum creatinine, vancomycin peak and trough levels, and clinical outcomes were monitored.

Results: Twenty patients were included in the study. There were no significant differences in baseline data between the two groups. Among the 20 patients, the mean AUC/MIC was higher in the intervention group (345.80 ± 31.95) compared to the control group (251.43 ± 83.10, P = 0.005), although the therapeutic target was not achieved in either group. Despite the lower AUC in the control group, mortality rates, AKI progression, and the need for hemodialysis were comparable between groups (P = 0.29).

Conclusions: Full-dose vancomycin increases the likelihood of achieving PD targets like AUC/MIC in AKI patients. Larger studies are warranted to confirm these findings.

Background: Artemisia biennis is a weed of several crops, but some valuable biological effects have been reported from its various extracts.

Objectives: The present phytochemical study was carried out on the dichloromethane (DCM) extract of the aerial parts of A. biennis. The prominent cytotoxic and antifungal activities of this extract were previously reported.

Methods: The DCM extract was fractionated using vacuum-liquid chromatography (VLC). The selected fractions were purified by VLC and semi-preparative high-performance liquid chromatography (HPLC). The structures of the isolated compounds were characterized by comprehensive spectroscopic analyses.

Results: Two acetylenic metabolites [(E)-en-yn-dicycloether, (Z)-en-yn-dicycloether], and a 2-phenoxychromone derivative (6-demethoxy-4'-O-methylcapillarisin) were isolated from the DCM extract of A. biennis aerial parts.

Conclusions: These two acetylenic metabolites have exhibited various effects on biological systems. The results of this study are in accordance with the reported cytotoxic and antifungal activities of the DCM extract of A. biennis. The chemotaxonomic significance of the isolated compounds is also notable.

Background: Acinetobacter baumannii-induced nosocomial pneumonia and its associated biofilm infections pose significant clinical challenges due to high rates of antibiotic resistance. Traditional antibiotic treatments encounter numerous obstacles, making antimicrobial peptides (AMPs) a promising alternative for controlling such pathogens. The emergence of multidrug-resistant strains necessitates the exploration of innovative therapeutic strategies.

Objectives: We recently designed a novel hybrid peptide, M-PEX12, which exhibits antimicrobial activity and low toxicity in vitro. To confirm its therapeutic potential, we evaluated it in both in vitro and in vivo settings.

Methods: M-PEX12 was evaluated using time-kill kinetics, thermal stability, reactive oxygen species (ROS) generation, biofilm inhibition assays, scanning electron microscopy (SEM), cytotoxicity tests, and virulence gene expression analysis. Its in vivo activity against A. baumannii was also assessed in an animal model.

Results: The time-kill kinetics assay indicated that exposure to M-PEX12 at 1x minimum inhibitory concentration (MIC) (33/154) and 2x MIC resulted in over 95% reduction in bacterial populations within 30 minutes. Notably, the bacteria did not develop resistance to increased temperatures. M-PEX12 effectively disrupted biofilm formation at various concentrations. Field emission SEM revealed significant ultrastructural deformities in A. baumannii cell walls. Treatment with M-PEX12 increased production of intracellular ROS and decreased cell viability in a concentration-dependent manner. Cytotoxicity assays showed no significant effect on HEK293 cell viability. Additionally, expression levels of omp33, csuE, bfmR, and ompA were significantly reduced. The antimicrobial efficacy of M-PEX12 was confirmed in vivo.

Conclusions: M-PEX12 exhibited significant antimicrobial activity and low toxicity in a mouse model, suggesting its potential as a treatment for drug-resistant bacterial infections.

Background: Liver cancer is increasing in different parts of the world and is the fourth leading cause of cancer death globally.

Objectives: The present study aims to synthesize and analyze the characterization of gold nanoparticles (AuNPs) synthesized by Cichorium intybus extract and evaluate their antioxidant and cellular toxicity activity against liver cancer cells (HepG2).

Methods: The synthesized AuNPs were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and fourier-transform infrared spectroscopy (FTIR). The antioxidant activity of the nanoparticles was assessed using the DPPH test, and their cytotoxicity activity was analyzed using the MTT method.

Results: The results indicate that the AuNPs are crystalline materials with a particle size of less than 100 nm, with a mean particle size of 23.94 nm. The FTIR study reveals the presence of biochemical groups that act as reducing factors. The results demonstrate that antioxidant activity increases with concentration, with 87% inhibition of DPPH free radical scavenging observed at 250 µg/mL. Cell toxicity results in liver cancer cell lines (HepG2) demonstrated significant cytotoxicity in a time- and dose-dependent manner. The percentage of cell viability at a concentration of 1000 µg/ml after 24, 48, and 72 hours was determined to be 45%, 51%, and 22%, respectively.

Conclusions: The present study revealed the simple cost-effective and environmentally friendly method that could be employed from food to pharmaceutical industries.

Background: Hepatic ischemia-reperfusion injury (HIRI) significantly affects the prognosis of liver surgery, such as hepatocellular carcinoma resection and liver transplantation. However, the pathogenesis of HIRI has not been fully elucidated, and prevention and treatment strategies remain challenging.

Methods: A mouse model of HIRI was established, and schisandrin B (Sch B) was used to intervene in HIRI. The effect of Sch B on HIRI was assessed using hematoxylin and eosin (HE) staining, quantitative polymerase chain reaction (qPCR), Western blot (WB), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA).

Results: The expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of the HIRI mouse model was significantly increased, indicating the successful construction of the HIRI mouse model. In the Sch B intervention group, serum ALT and AST levels were significantly decreased. Hematoxylin and eosin staining and qPCR results demonstrated that Sch B could reduce HIRI in mice. The qPCR and immunohistochemistry showed that Sch B reduced HIRI in mice by decreasing the expression of autophagy-related factors Beclin-1 and LC3-II.

Conclusions: Additionally, qPCR and immunohistochemical results indicated that Sch B reduced HIRI by decreasing the expression of autophagy-related factors (Beclin-1 and LC3-II) and hepatocyte damage-related factors (caspase-3, caspase-9, and Bax), thereby reducing HIRI in mice. The results of electron microscopy, immunohistochemistry, and qPCR confirmed that Sch B could reduce autophagy and alleviate HIRI.

Background: The present study aimed to determine the pharmacokinetic parameters and bioequivalence of the test medicinal product, apixaban 5 mg tablet, and its reference product, Eliquis^®, in healthy male and female subjects under a fasted state.

Methods: Before in vivo evaluation, the quality control parameters of the products were evaluated and compared. This study was a single-dose, double-blind, 2-sequence, crossover, 2-period, randomized bioequivalence and pharmacokinetic study in 24 healthy individuals with a two-week washout period between doses. A series of blood samples were obtained over 48 hours after dose administration, and the samples were analyzed for their apixaban content using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. The pharmacokinetic parameters were computed using non-compartmental analysis.

Results: Both products passed the in vitro quality control criteria. Following administration of the apixaban tablet, the area under curve (AUC)_0-t, AUC_0-∞, and maximum plasma concentration (C_max) mean values for the test product were 1284.0 ng.h/mL, 1368.2 ng.h/mL, and 157.4 ng/mL, respectively, and for the reference product were 1310.6 ng.h/mL, 1406.5 ng.h/mL, and 157.6 ng/mL, respectively. The 90% confidence intervals (CI) of the geometric mean ratio for AUC_0-t (91.4 - 105.9), AUC_0-∞ (92.9 - 106.9), and C_max (87.1 - 101.9) fell within the predefined accepted range of 80% - 125%. No serious adverse events were observed.

Conclusions: The test product (apixaban 5 mg tablet) and reference product (Eliquis^®) achieved regulatory requirements for bioequivalence in healthy individuals under a fasted state.

Background: Wound healing and antibiotic resistance of pathogenic microbes have become global issues with serious consequences for the treatment of infectious diseases.

Objectives: The present study aimed to evaluate the antibacterial, anti-inflammatory, angiogenic, and wound healing properties of copper nanoparticles (CuNPs) synthesized using Lupinus arcticus extract.

Methods: The green synthesis was conducted using the precipitation method. The antibacterial activity of CuNPs against both methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains was evaluated. The effects of CuNPs on protein leakage, the expression levels of biofilm-related genes [e.g., intracellular adhesion A (icaA), intracellular adhesion D (icaD), and elastin-binding protein (EbpS) genes] in MRSA, as well as its impact on wound healing, angiogenesis, and anti-inflammatory effects, were assessed.

Results: The CuNPs exhibited a spherical shape with dimensions ranging from 10 to 85 nm. Both CuNPs alone and in combination with gentamicin (GNT) inhibited biofilm formation in MRSA, with minimum biofilm inhibitory concentration (MBIC₅₀) values of 6.6 µg/mL and 0.50 µg/mL for MRSA, respectively. The CuNPs significantly (P < 0.05) downregulated the expression levels of icaA, icaD, and EbpS in MRSA, particularly at half the minimum inhibitory concentration (1/2 MIC) and the minimum inhibitory concentration (MIC). Additionally, CuNPs markedly (P < 0.001) increased protein leakage in MRSA. The CuNPs demonstrated potent in vitro wound healing effects, promoting fibroblast cell proliferation and wound closure in a dose-dependent manner. Our results indicated a significant (P < 0.05) increase in the expression of HLA-G5 and VEGF-A genes in cells exposed to CuNPs. Furthermore, CuNPs reduced the expression levels of inflammatory genes in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (P < 0.05).

Conclusions: The findings of this experimental test indicate that CuNPs, particularly in conjunction with GNT, exhibits promising antibacterial effects against MRSA without causing cytotoxicity to normal cells. This study also demonstrated that green-synthesized CuNPs possesses significant wound-healing properties through its antibacterial activity, inhibition of biofilm formation, induction of angiogenesis, and reduction of inflammation. However, further experiments are necessary to elucidate the precise mechanisms of action and potential toxicity of CuNPs.

Background: Breast cancer is among the most prevalent cancers in women and is the leading cause of mortality among women worldwide. Although a definitive cure for breast cancer remains elusive, essential fatty acids offer a promising therapeutic avenue.

Objectives: The present study aimed to synthesize 16 derivatives of docosahexaenoic acid (DHA) and linoleic acid (LA) and evaluate their anti-cancer properties in vitro.

Methods: Fourteen derivatives of LA and DHA were synthesized using a coupling method, while two ethylenediamine derivatives were synthesized via an ester intermediate. Molecular modeling was conducted using AutoDock Vina software. The cytotoxic effects of all compounds were assessed using the MTT assay on breast adenocarcinoma (MCF-7) cells. The mechanism of cell death induction by derivatives with the most favorable EC₅₀ values was determined through annexin V-FITC/PI flow cytometry analysis, focusing on early and late apoptosis.

Results: Docking results revealed that these compounds effectively interact with residues in the PTPB1 active site. All synthesized DHA and LA derivatives demonstrated cytotoxic effects on the MCF-7 cell line, with no significant cytotoxicity observed in normal human dermal fibroblasts (HDFs). Compounds D3 and L3, with EC₅₀ values of 15.96 ± 2.89 μM and 24.64 ± 1.81 μM, respectively, were identified as the most potent anti-cancer compounds among the derivatives.

Conclusions: The findings indicate that these functional fatty acid derivatives significantly reduce cancer cell viability. In addition to necrosis, compounds L3 and D3 induced apoptosis, with apoptosis rates of 20.5% and 47.1%, respectively.