Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used due to their profound efficacy in glycemic control and weight management. Within real-world contexts, the manifestation of certain psychiatric adverse events (AEs) has been observed, which is potentially linked to the administration of GLP-1 RAs. The objective of this study was to undertake a comprehensive investigation and characterization of the psychiatric AEs associated with GLP-1 RAs. Methods: We retrieved reports of AEs associated with treatment with GLP-1 RAs during the period from the first quarter (Q1) of 2004 to Q1 2023 from the FDA Adverse Event Reporting System (FAERS) database. Descriptive analysis was performed to examine the clinical characteristics and time to onset of the psychiatric AEs caused by GLP-1 RAs. Moreover, disproportionality analyses were performed using the reporting odds ratio (ROR) to identify GLP-1 RA-related psychiatric AEs. Results: A total of 8,240 reports of psychiatric AEs were analyzed out of 181,238 AE reports with treatment with GLP-1 RAs. Among these cases, a higher percentage was represented by women compared to men (65.89% vs. 30.96%). The median age of these patients was 56 years, with an interquartile range (IQR) of 48-67 years, based on data available in 286 case reports. This study showed that the median time to onset of the overall GLP-1 RA-related AEs was 31 days (IQR = 7-145.4 days), which varied among GLP-1 RA regimens. Specifically, exenatide had a significantly longer onset time at 45 days (IQR = 11-213 days), with statistically significant differences from the onset times of the other five GLP-1 RAs (p< 0.0001). Moreover, eight categories of psychiatric AEs, namely, nervousness (ROR = 1.97, 95% CI = 1.85-2.11), stress (ROR = 1.28, 95% CI = 1.19-1.38), eating disorder (ROR = 1.57, 95% CI = 1.40-1.77), fear of injection (ROR = 1.96, 95% CI = 1.60-2.40), sleep disorder due to general medical condition-insomnia type (ROR = 2.01, 95% CI = 1.60-2.52), binge eating (ROR = 2.70, 95% CI = 1.75-4.16), fear of eating (ROR 3.35, 95% CI = 1.65-6.78), and self-induced vomiting (ROR = 3.77, 95% CI = 1.77-8.03), were defined as GLP-1 RA-related psychiatric AEs through disproportionality analysis. Conclusion: Our findings demonstrate a significant association between GLP-1 RAs and the development of specific psychiatric AEs. Despite the observational nature of this pharmacovigilance study and the inherent limitations of the FAERS database, our preliminary findings in this work could provide a better basis for understanding the potential psychiatric AEs that may occur with GLP-1 RA treatment, assisting clinicians to focus on these AEs and provide early intervention for optimal risk management.

The role of alkyl chain length in the melt and solution crystallization of paliperidone aliphatic prodrugs.

Fatty acid-derivative prodrugs have been utilized extensively to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of active pharmaceutical ingredients. However, to our knowledge, the crystallization behavior of prodrugs modified with different fatty acids has not been explored. In the present work, a series of paliperidone aliphatic prodrugs with alkyl chain lengths ranging from C4 to C16 was investigated with respect to crystal structure, crystal morphology and crystallization kinetics. The paliperidone derivatives exhibited isostructural crystal packing, despite the different alkyl chain lengths, and crystallized with the dominant (100) face in both melt and solution. The rate of crystallization for paliperidone derivatives in the melt increases with alkyl chain length owing to greater molecular mobility. In contrast, the longer chains prolong the nucleation induction time and reduce the crystal growth kinetics in solution. The results show a correlation between difficulty of nucleation in solution and the interfacial energy. This work provides insight into the crystallization behavior of paliperidone aliphatic prodrugs and reveals that the role of alkyl chain length in the crystallization behavior has a strong dependence on the crystallization method.

Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs.

PURPOSE: The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs. METHOD: The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms. RESULT: The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release. CONCLUSION: Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.

Etiology and antimicrobial resistance of secondary bacterial infections in patients hospitalized with COVID-19 in Wuhan, China: a retrospective analysis.

BACKGROUND: A considerable proportion of patients hospitalized with coronavirus disease 2019 (COVID-19) acquired secondary bacterial infections (SBIs). The etiology and antimicrobial resistance of bacteria were reported and used to provide a theoretical basis for appropriate infection therapy. METHODS: This retrospective study reviewed electronic medical records of all the patients hospitalized with COVID-19 in the Wuhan Union Hospital between January 27 and March 17, 2020. According to the inclusion and exclusion criteria, patients who acquired SBIs were enrolled. Demographic, clinical course, etiology, and antimicrobial resistance data of the SBIs were collected. Outcomes were also compared between patients who were classified as severe and critical on admission. RESULTS: Among 1495 patients hospitalized with COVID-19, 102 (6.8%) patients had acquired SBIs, and almost half of them (49.0%, 50/102) died during hospitalization. Compared with severe patients, critical patients had a higher chance of SBIs. Among the 159 strains of bacteria isolated from the SBIs, 136 strains (85.5%) were Gram-negative bacteria. The top three bacteria of SBIs were A. baumannii (35.8%, 57/159), K. pneumoniae (30.8%, 49/159), and S. maltophilia (6.3%, 10/159). The isolation rates of carbapenem-resistant A. baumannii and K. pneumoniae were 91.2 and 75.5%, respectively. Meticillin resistance was present in 100% of Staphylococcus aureus and Coagulase negative staphylococci, and vancomycin resistance was not found. CONCLUSIONS: SBIs may occur in patients hospitalized with COVID-19 and lead to high mortality. The incidence of SBIs was associated with the severity of illness on admission. Gram-negative bacteria, especially A. baumannii and K. pneumoniae, were the main bacteria, and the resistance rates of the major isolated bacteria were generally high. This was a single-center study; thus, our results should be externally examined when applied in other institutions.

Magnetic solid-phase extraction coupled with UHPLC-MS/MS for four antidepressants and one metabolite in clinical plasma and urine samples.

Aim: Routine therapeutic drug monitoring is highly recommended since common antidepressant combinations increase the risk of drug-drug interactions or overlapping toxicity. Materials & methods: A magnetic solid-phase extraction by using C18-functionalized magnetic silica nanoparticles (C18-Fe3O4@SiO2 NPs) as sorbent was proposed for rapid extraction of venlafaxine, paroxetine, fluoxetine, norfluoxetine and sertraline from clinical plasma and urine samples followed by ultra-HPLC-MS/MS assay. Results: The synthesized C18-Fe3O4@SiO2 NPs showed high magnetization and efficient extraction for the analytes. After cleanup by magnetic solid-phase extraction, no matrix effects were found in plasma and urine matrices. The analytes showed LODs among 0.15-0.75 ng ml-1, appropriate linearity (R ≥ 0.9990) from 2.5 to 1000 ng ml-1, acceptable accuracies 89.1-110.9% with precisions ≤11.0%. The protocol was successfully applied for the analysis of patients' plasma and urine samples. Conclusion: It shows high potential in routine therapeutic drug monitoring of clinical biological samples.

Preparation of magnetic ODS-PAN thin-films for microextraction of quetiapine and clozapine in plasma and urine samples followed by HPLC-UV detection.

In this study, conventional thin-film microextraction (TFME) was endowed with magnetic by introducing superparamagnetic SiO2@Fe3O4 nanoparticles in thin-films. Novel magnetic octadecylsilane (ODS)-polyacrylonitrile (PAN) thin-films were prepared by spraying, and used for the microextraction of quetiapine and clozapine in plasma and urine samples, followed by the detection of HPLC-UV. The influencing factors on the extraction efficiency of magnetic ODS-PAN TFME, including pH, extraction time, desorption solvent, desorption time, and ion strength were investigated systematically. Under the optimal conditions, both analytes showed good linearity over ranges of 0.070-9.000µgmL(-1) and 0.012-9.000µgmL(-1) in plasma and urine samples, respectively, with correlation coefficients (R(2)) above 0.9990. Limits of detection (LODs) for quetiapine in plasma and urine samples were 0.013 and 0.003µgmL(-1), respectively. LODs for clozapine in plasma and urine samples were 0.015 and 0.003µgmL(-1), respectively. The relative standard deviations (RSDs) for quetiapine and clozapine were less than 9.23%. After the validation, the protocol was successfully applied for the determination of quetiapine and clozapine in patients' plasma and urine samples with satisfactory recoveries between 99-110%. The proposed magnetic ODS-PAN TFME was very simple, fast and easy to handle. It showed high potential as a powerful pretreatment technology for routine therapeutic drug monitoring (TDM) in plasma and urine samples.

Neuroprotective effect of peptides extracted from walnut (Juglans Sigilata Dode) proteins on Aß25-35-induced memory impairment in mice.

Alzheimer's disease (AD) is one of the major neurodegenerative disorders of the elderly, which is characterized by the accumulation and deposition of amyloid-beta (Aß) peptide in human brains. Oxidative stress and neuroinflammation induced by Aß in brain are increasingly considered to be responsible for the pathogenesis of AD. The present study aimed to determine the protective effects of walnut peptides against the neurotoxicity induced by Aß25-35 in vivo. Briefly, the AD model was induced by injecting Aß25-35 into bilateral hippocampi of mice. The animals were treated with distilled water or walnut peptides (200, 400 and 800 mg/kg, p.o.) for five consecutive weeks. Spatial learning and memory abilities of mice were investigated by Morris water maze test and step-down avoidance test. To further explore the underlying mechanisms of the neuroprotectivity of walnut peptides, the activities of superoxide dismutase (SOD), glutathione (GSH), acetylcholine esterase (AChE), and the content of malondialdehyde (MDA) as well as the level of nitric oxide (NO) in the hippocampus of mice were measured by spectrophotometric method. In addition, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß) and IL-6 in the samples were determined using ELISA. The hippocampal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κB) were evaluated by Western blot analysis. The results showed that walnut peptides supplementation effectively ameliorated the cognitive deficits and memory impairment of mice. Meanwhile, our study also revealed effective restoration of levels of antioxidant enzymes as well as inflammatory mediators with supplementation of walnut peptides (400 or 800 mg/kg). All the above findings suggested that walnut peptides may have a protective effect on AD by reducing inflammatory responses and modulating antioxidant system.

Comparison of two thin-film microextractions for the analysis of estrogens in aqueous tea extract and environmental water samples by high performance liquid chromatography-ultraviolet detection.

Two thin-film microextractions (TFME), octadecylsilane (ODS)-polyacrylonitrile (PAN)-TFME and polar enhanced phase (PEP)-PAN-TFME have been proposed for the analysis of bisphenol-A, diethylstilbestrol and 17ß-estradiol in aqueous tea extract and environmental water samples followed by high performance liquid chromatography-ultraviolet detection. Both thin-films were prepared by spraying. The influencing factors including pH, extraction time, desorption solvent, desorption volume, desorption time, ion strength and reusability were investigated. Under the optimal conditions, the two TFME methods are similar in terms of the analytical performance evaluated by standard addition method. The limits of detection for three estrogens in environmental water and aqueous tea extract matrix ranged from 1.3 to 1.6 and 2.8 to 7.1 ng mL(-1) by the two TFME methods, respectively. Both approaches were applied for the analysis of analytes in real aqueous tea extract and environmental water samples, presenting satisfactory recoveries ranged from 87.3% to 109.4% for the spiked samples.

Preparation of magnetic molecularly imprinted polymers for selective isolation and determination of kaempferol and protoapigenone in Macrothelypteris torresiana.

Novel uniform-sized magnetic molecularly imprinted polymers (MMIPs) were synthesized for selective recognition of active antitumor ingredients of kaempferol (KMF) and protoapigenone (PA) in Macrothelypteris torresiana (M. torresiana) by surface molecular imprinting technique in this study. Super paramagnetic core-shell nanoparticles (γ-MPS-SiO2@Fe3O4) were used as seeds, KMF as template molecule, acrylamide (AM) as functional monomer, and N, N'-methylene bisacrylamide (BisAM) as cross-linker. The prepared MMIPs were characterized by X-ray diffraction (XRD), Fourier transform infrared spectrum (FTIR), transmission electron microscopy (TEM) and thermo-gravimetric analysis (TGA), respectively. The recognition capacity of MMIPs was 2.436 times of non-imprinted polymers. The adsorption results based on kinetics and isotherm analysis were in accordance with the pseudo-second-order model (R (2)=0.9980) and the Langmuir adsorption model (R (2)=0.9944). The value of E (6.742 kJ/mol) calculated from the Dubinin-Radushkevich isotherm model suggested that the physical adsorption via hydrogen-bonding might be predominant. The Scatchard plot showed a single line (R (2)=0.9172) and demonstrated the homogeneous recognition sites on MMIPs for KMF. The magnetic solid phase extraction (MSPE) based on MMIPs as sorbent was established for fast and selective enrichment of KMF and its structural analogue PA from the crude extract of M. torresiana and then KMF and PA were detected by HPLC-UV. The established method showed good performance and satisfactory results for real sample analysis. It also showed the feasibility of MMIPs for selective recognition of active structural analogues from complex herbal extracts.