A review on reactive oxygen species-induced mechanism pathways of pharmaceutical waste degradation: Acetaminophen as a drug waste model.

Innately designed to induce physiological changes, pharmaceuticals are foreknowingly hazardous to the ecosystem. Advanced oxidation processes (AOPs) are recognized as a set of contemporary and highly efficient methods being used as a contrivance for the removal of pharmaceutical residues. Since reactive oxygen species (ROS) are formed in these processes to interact and contribute directly toward the oxidation of target contaminant(s), a profound insight regarding the mechanisms of ROS leading to the degradation of pharmaceuticals is fundamentally significant. The conceptualization of some specific reaction mechanisms allows the design of an effective and safe degradation process that can empirically reduce the environmental impact of the micropollutants. This review mainly deliberates the mechanistic reaction pathways for ROS-mediated degradation of pharmaceuticals often leading to complete mineralization, with a focus on acetaminophen as a drug waste model.

Self-medication among Basic Science Medical Students of a Tertiary Care Centre: A Descriptive Cross-sectional Study.

INTRODUCTION: Self-medication is using drugs to treat self-diagnosed signs or symptoms of oneself or others. Being closer to pharmacology and pathology, medical students have been more prone to it. The study aimed to determine the prevalence of self-medication among basic sciences medical students in a tertiary care centre in Kathmandu. METHODS: A descriptive cross-sectional study was conducted among basic science students from 15 February 2023 to 14 March 2023 after obtaining ethical approval from the Institutional Review Committee (Reference number: 04122022/04). A convenience sampling method was used. Data were collected online and analysed. Point estimate at 95% confidence interval was calculated. RESULTS: Among 322 basic science medical students the prevalence of self-medication was 218 (67.70%) (64.81-70.59 at 95% Confidence Interval). Fever was the most common condition treated by self-medication 106 (48.62%) and paracetamol was the most common medication 93 (42.66%). Of those who engaged in self-medication, 97 (44.50%) did so to save time. Moreover, within this group, 67 (30.73%) experienced adverse drug reactions, leading 37 (16.97%) of these students to visit a private doctor. Additionally, 138 (63.30%) refrained from prescribing medication to their family and friends. CONCLUSIONS: Self-medication among basic science medical students was found to be lower in comparison to other studies done in similar settings.

Pain after laparoscopic endometriosis-specific vs. hysterectomy surgeries: A retrospective cohort analysis.

OBJECTIVES: To evaluate pain perception and analgesic use between patients who underwent endometriosis-specific laparoscopic surgery compared to laparoscopic hysterectomy. MATERIAL AND METHODS: This retrospective cohort study included women diagnosed with endometriosis who underwent laparoscopic surgery from 1/2019 to 11/2022. The control group consisted of premenopausal women who underwent laparoscopic hysterectomy, which was considered a similarly extensive surgery. Demographics, preoperative and post-operative data were compared between groups. Post-operative pain scores on a visual analogue scale (VAS) between 0 (no pain) and 10 (worst pain) were compared between groups for each post-operative day (POD). Standard pain relief analgesia on POD 0-1 included fixed intravenous treatment with paracetamol and intramuscular diclofenac. The need for additional analgesics (morphine or dipyrone) beyond the standard pain relief protocol was compared between groups. RESULTS: Among 200 patients who underwent laparoscopic surgery, 100 (50%) were in the endometriosis group and 100 (50%) in the hysterectomy group. The endometriosis group was characterized by younger age and lower parity (both, p<0.001). There was no significant difference between the groups in mean VAS scores for each post-operative day. However, among patients who needed additional analgesics beyond the standard protocol on POD 1, a higher percentage of women in the endometriosis group used opioids rather than milder analgesics, as compared to controls (1% vs. 0.2%, respectively, p = 0.03). CONCLUSION: Increased post-operative morphine use was observed in patients with endometriosis following laparoscopic surgery, despite no significant difference in mean VAS scores during the post-operative days. These findings suggest that personalized pain relief protocols should be adjusted for women with endometriosis.

Aloperine Ameliorates Acetaminophen-Induced Acute Liver Injury through HMGB1/TLR4/NF-κB and NLRP3/Inflammasome Pathway.

Purpose: Aloperine (ALO), an alkaloid isolated from Sophora alopecuroides L., possesses multiple pharmacological activities and holds a promise potential for the treatment of various clinical conditions, including skin hypersensitivity, cancer, and inflammatory disorders. The purpose of this study was to investigate the role of ALO in acetaminophen (N-acetyl-para-aminophenol (APAP))-induced acute liver injury and its underlying mechanisms. Materials and Methods: An animal model of acute liver injury was induced by intraperitoneal injection of APAP (150 mg/kg). Prior to APAP injection, ALO (40 mg/kg) was administered daily for 7 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels were then measured using an automated chemical analyzer. Histopathological changes were evaluated using hematoxylin and eosin staining. Oxidative stress levels were measured by detecting superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). Pro-inflammatory cytokines were detected in serum and liver tissues using ELISA and quantitative real-time polymerase chain reaction (q-PCR). The expression of members of the HMGB1/TLR4/NF-κB signaling pathway and NLRP3 inflammasome were determined by Western blot and/or q-PCR. In addition, the expression and location of NLRP3, cleaved caspase-1, high-mobility group box 1 (HMGB1), and phosphorylated p65 (p-p65) were detected by immunofluorescence. Results: Pretreatment with ALO significantly protected mice from APAP-induced acute liver injury, with decreased MDA content, and significantly increased GSH and SOD activities. Furthermore, ALO pretreatment reduced the release of pro-inflammatory cytokines (IL-1ß and TNF-α) and decreased the expression of caspase-1, cleaved caspase-1, and NLRP3. In addition, ALO pretreatment also inhibited the activation of the HMGB1/TLR4/NF-κB signaling pathway. Conclusion: Taken together, ALO can ameliorate APAP-induced acute liver injury by inhibiting oxidative stress, inflammation by inhibiting the HMGB1/TLR4/NF-κB, and NLRP3/inflammasome pathway.

The Prophylactic Effect of Acetaminophen and Caffeine on Post Dural Puncture Headache after Spinal Anesthesia for Cesarean Section: A Randomized Double-Blind Clinical Trial.

Background: Post-dural puncture headache (PDPH) is the most common complication following spinal anesthesia among parturients undergoing cesarean section surgery. The purpose of this study was to evaluate the effectiveness of acetaminophen and caffeine in preventing PDPH. Methods: This double-blind, randomized clinical trial was conducted on 96 obstetric women, who were candidates for elective cesarean section. Following the randomization of participants into two groups, participants in the intervention group received tablets of acetaminophen (500 mg)+caffeine (65 mg), and participants in the control group received placebo tablets orally 2 hours before spinal anesthesia induction and then every 6 hours after surgery up to 24 hours. All parturients were evaluated for frequency and intensity of PDPH every 6 hours until 24 hours after surgery and then 48 and 72 hours after surgery. Overall satisfaction during the first 72 hours of postpartum was evaluated. The data were analyzed using SPSS software. P<0.05 was considered statistically significant. Results: Participants in the intervention group were 70% less likely to experience PDPH after spinal anesthesia (OR=0.31 P=0.01, 95% CI [0.12-0.77]). They also experienced significantly milder headaches 18 hours, 48 hours, and 72 hours later. Participants in the intervention group reported higher levels of satisfaction at the end of the study (P=0.01). No side effects related to the intervention were reported. Conclusion: Prophylactic administration of acetaminophen+caffeine decreases 70% the risk of PDPH and significantly attenuates pain intensity in obstetric patients who underwent spinal anesthesia for cesarean section.

Eed-dependent histone modification orchestrates the iNKT cell developmental program alleviating liver injury.

Polycomb repressive complex 2 (PRC2) is an evolutionarily conserved epigenetic modifier responsible for tri-methylation of lysine 27 on histone H3 (H3K27me3). Previous studies have linked PRC2 to invariant natural killer T (iNKT) cell development, but its physiological and precise role remained unclear. To address this, we conditionally deleted Eed, a core subunit of PRC2, in mouse T cells. The results showed that Eed-deficient mice exhibited a severe reduction in iNKT cell numbers, particularly NKT1 and NKT17 cells, while conventional T cells and NKT2 cells remained intact. Deletion of Eed disrupted iNKT cell differentiation, leading to increased cell death, which was accompanied by a severe reduction in H3K27me3 levels and abnormal expression of Zbtb16, Cdkn2a, and Cdkn1a. Interestingly, Eed-deficient mice were highly susceptible to acetaminophen-induced liver injury and inflammation in an iNKT cell-dependent manner, highlighting the critical role of Eed-mediated H3K27me3 marks in liver-resident iNKT cells. These findings provide further insight into the epigenetic orchestration of iNKT cell-specific transcriptional programs.

Material-Sparing Approach to Predict Tablet Capping Under Processing Compression Conditions Based on Mechanical and Molecular Properties Derived from Compaction Simulation and Crystal Structural Analysis.

Present study evaluates the usability of compaction simulation-based mechanical models as a material-sparing approach to predict tablet capping under processing compression conditions using Acetaminophen (APAP) and Ibuprofen (IBU). Measured mechanical properties were evaluated using principal component analysis (PCA) and principal component regression (PCR) models. PCR models were then utilized to predict the capping score (CS) from compression pressure (CP). APAP formulations displayed a quadratic correlation between CS and CP, with CS rank order following CP of 200MPa < 300MPa < 100MPa, indicating threshold compression pressure (TCP) limit between 200 and 300 MPa, resulting in higher CS at 300 than 200 MPa regardless of increased CP. IBU formulations displayed a linear correlation between CS and CP, with CS rank order following CP of 100MPa < 200MPa < 300MPa, indicating TCP limit between 100 and 200 MPa, resulting in higher CS at 200 and 300 than 100 MPa regardless of increased CP. Molecular models were developed as validation methods to predict capping from CP. Measured XRPD patterns of compressed tablets were linked with calculated Eatt and d-spacing of slip planes and analyzed using variable component least square methods to predict TCP triggering cleavage in slip planes and leading to capping. In APAP and IBU, TCP values were predicted at 245 and 175 MPa, meaning capped tablets above these TCP limits regardless of increased CP. A similar trend was observed in CS predictions from mechanical assessment, confirming that compaction simulation-based mechanical models can predict capping risk under desired compression conditions rapidly and accurately.

Exploring the phytochemicals, antioxidant properties, and hepatoprotective potential of Moricandia sinaica leaves against paracetamol-induced toxicity: Biological evaluations and in Silico insights.

Thirteen components were identified in the methanol extract of Moricandia sinaica leaves (MSLE) through analysis utilizing HPLC-ESI-MS/MS., including flavonoids, anthocyanins, phenolic acids, and fatty acids. The methanol extract of M. sinaica leaves contained total phenolics and flavonoids (59.37 ± 2.19 mg GAE/g and 38.94 ± 2.72 mg QE/g), respectively. Furthermore, it revealed in vitro antioxidant properties as determined by the DPPH and FRAP assays, with respective IC50 values of 10.22 ± 0.64 and 20.89 ± 1.25 µg/mL. The extract exhibited a notable hepatoprotective effect in rats who experienced paracetamol-induced hepatotoxicity. When a dose of 250 mg/kg was given, there was a 52% reduction in alanine transaminase and a 30% reduction in aspartate transaminase compared to the group with the disease. Furthermore, it demonstrated a 3.4-fold, 2.2-fold, and 2.6-fold increase in superoxide dismutase, non-protein sulfhydryl, and glutathione peroxidase, respectively. In addition, it demonstrated a 68% decrease in lipid peroxide levels compared to the group with paracetamol-induced condition. The verification was conducted using a histological study, which identified improved liver histology with a small number of distended hepatocytes. Moreover, in silico studies focused on the enzymes NADPH oxidase, butyrylcholinesterase, and tyrosinase as the targets for the major compounds. In conclusion, MSLE showed promising hepatoprotective and antioxidant activities due to its richness in antioxidant metabolites.

Application of physiological network mapping in the prediction of survival in critically ill patients with acute liver failure.

Reduced functional connectivity of physiological systems is associated with poor prognosis in critically ill patients. However, physiological network analysis is not commonly used in clinical practice and awaits quantitative evidence. Acute liver failure (ALF) is associated with multiorgan failure and mortality. Prognostication in ALF is highly important for clinical management but is currently dependent on models that do not consider the interaction between organ systems. This study aims to examine whether physiological network analysis can predict survival in patients with ALF. Data from 640 adult patients admitted to the ICU for paracetamol-induced ALF were extracted from the MIMIC-III database. Parenclitic network analysis was performed on the routine biomarkers using 28-day survivors as reference population and network clusters were identified for survivors and non-survivors using k-clique percolation method. Network analysis showed that liver function biomarkers were more clustered in survivors than in non-survivors. Arterial pH was also found to cluster with serum creatinine and bicarbonate in survivors compared with non-survivors, where it clustered with respiratory nodes indicating physiologically distinctive compensatory mechanism. Deviation along the pH-bicarbonate and pH-creatinine axes significantly predicts mortality independent of current prognostic indicators. These results demonstrate that network analysis can provide pathophysiologic insight and predict survival in critically ill patients with ALF.

Pentagalloylglucose alleviates acetaminophen-induced acute liver injury by modulating inflammation via cGAS-STING pathway.

BACKGROUND: The cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear. MATERIALS AND METHODS: A cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI. RESULTS: PGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1. CONCLUSIONS: PGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy.

Hepato and Nephro protective potentials of lyophilized juice of Citrus reticulata L. fruit against paracetamol induced toxicity in rats.

This study scrutinized the phytochemical composition, curative, hepato and nephro protective effect of different doses of lyophilized juice of Citrus reticulata fruit against paracetamol induced toxicity. Phytochemical screening and RP-HPLC analysis were conducted to quantify total polyphenols and flavonoids respectively. For evaluation of in vivo curative and protective effects, thirty six rats were randomly divided into six groups. In first four groups 1, II, III and IV paracetamol 75mg/kg, i.p, 150mg/kg, 250mg/kg and 500mg/kg p.o doses of lyophilized juice were administered to rats respectively. Blood samples were withdrawn at 0, 24, 48 and 72 hours in paracetamol treated rats. For screening of hepato and nephro protective effect Group V and VI were fed on lyophilized juice (250mg/kg and 500mg/kg p.o) for seven days and on 8th day blood samples were collected at 0,24,48 and 72 hours. Hepatic and renal biomarkers were monitored. Phytochemical analysis revealed the presence of total polyphenols (20.7±0.3GAEmg/g) and flavonoid contents (21.2±0.4QE mg/g). RP-HPLC also confirmed the presence of Myricetin, Quercetin and Kaempferol in fruit juice. The lyophilized juice at 500mg/kg dose have shown profound decrease in paracetamol induced elevated serum levels of liver and kidney functions, which suggests a possible therapeutic role of its constituents in hepatic and kidney malfunctions.

Individual use of self-medication and other remedies in COVID-19 outpatients in Western-Pomerania.

We analyzed data from positively tested COVID-19 outpatients to describe self-medication with OTC drugs and use of other remedies against symptoms of SARS-CoV-2 infection. We specifically considered their type and frequency, as well as associations with patient characteristics, and reasons for use. Data were collected between May 1, 2020 and February 22, 2021 with two questionnaires in an observational cohort study with PCR-confirmed SARS-CoV-2-positive adult outpatients in the district of Western Pomerania in Germany. 523 out of 710 outpatients (74%; 340 women and 183 men) reported using drugs and other remedies to relieve COVID-19-symptoms. Overall, participants reported utilization of 1282 finished dosage products or remedies, including 213 different ingredients. In the population of 710 outpatients, utilization of ibuprofen (26%), acetaminophen (21%), metamizole (14%), and acetylsalicylic acid (10%) was most commonly reported. Phytopharmaceuticals, herbal and animal products as well as vitamins and minerals were also frequently reported. Among the 523 participants who used drugs and other remedies, most commonly mentioned reasons for use were headache (40%), other kinds of pain (e.g. myalgia; 37%), fever (24%) and cough (16%). Our analysis showed that a majority of the participants tried to alleviate COVID-19-symptoms using drugs and other remedies. Especially analgesic and antipyretic agents, followed by herbal medicines, were used very frequently.Trial registration: German Register for Clinical Studies DRKS00021672, first registration on December 1st, 2020.

Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.

Molecular Aspects of the Interactions between Selected Benzodiazepines and Common Adulterants/Diluents: Forensic Application of Theoretical Chemistry Methods.

Benzodiazepines are frequently encountered in crime scenes, often mixed with adulterants and diluents, complicating their analysis. This study investigates the interactions between two benzodiazepines, lorazepam (LOR) and alprazolam (ALP), with common adulterants/diluents (paracetamol, caffeine, glucose, and lactose) using infrared (IR) spectroscopy and quantum chemical methods. The crystallographic structures of LOR and ALP were optimized using several functionals (B3LYP, B3LYP-D3BJ, B3PW91, CAM-B3LYP, M05-2X, and M06-2X) combined with the 6-311++G(d,p) basis set. M05-2X was the most accurate when comparing experimental and theoretical bond lengths and angles. Vibrational and 13C NMR spectra were calculated to validate the functional's applicability. The differences between LOR's experimental and theoretical IR spectra were attributed to intramolecular interactions between LOR monomers, examined through density functional theory (DFT) optimization and quantum theory of atoms in molecules (QTAIM) analysis. Molecular dynamics simulations modeled benzodiazepine-adulterant/diluent systems, predicting the most stable structures, which were further analyzed using QTAIM. The strongest interactions and their effects on IR spectra were identified. Comparisons between experimental and theoretical spectra confirmed spectral changes due to interactions. This study demonstrates the potential of quantum chemical methods in analyzing complex mixtures, elucidating spectral changes, and assessing the structural stability of benzodiazepines in forensic samples.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

Quality Evaluation of Locally Manufactured Paracetamol Tablets in East Africa.

Background: Paracetamol, also known as acetaminophen, is categorized as an analgesic and antipyretic medication and is available as over the counter (OTC) medication. It is commonly used in conditions associated with pain and fever. There is a tendency for community to prefer using imported paracetamol tablets from Europe and United States than from Asia and Africa worrying of the quality of the products. Safety, effectiveness, and efficacy of a medicine can be guaranteed when its quality is reliable; however, there is limited data on the quality of locally manufactured paracetamol tablets, thus necessitating this study. Aim: This study is aimed at assessing the quality of paracetamol tablets 500 mg manufactured by local companies by evaluating their physical parameters, assay results, and dissolution profiles. The compliance of these tablets with the specifications outlined in the British Pharmacopoeia (BP) was analyzed. Additionally, a comparative dissolution test was conducted to assess dissolution profile for innovator product and generics. Method: Five different brands from East African countries with 76 tablets from each brand were compared with the innovator product regarding weight variation, hardness, friability, assay, and dissolution test based on the BP specifications. Results and discussion: All samples of paracetamol tablets 500 mg from the local manufacturers in this study met the specifications set by the BP for physical parameters, including weight variation, friability, hardness, and disintegration tests. The weight variation test, directly related to drug content variation, demonstrated compliance within the acceptable deviation of 5%. Similarly, the assay test, which determines the concentration of the active pharmaceutical ingredient (API), confirmed that all samples complied with the acceptable concentration range of 90%-110% for paracetamol. The dissolution test, assessing the percentage release of the API within a specified time, demonstrated that at 15 min, two samples (diodol and enamol) exhibited lower concentration releases than the required 80%, indicating potential delays in their bioavailability and onset of action. Conclusion: To conclude, all samples had good quality and they can be used for their therapeutic purposes.

Perioperative pain management intervention in older patients with hip fracture in an orthogeriatric unit. A controlled before/after study assessing an audit and feedback intervention (PAIN-AGE).

BACKGROUND: Postoperative pain delays ambulation, extends hospital stay, reduces the probability of recovery, and increases risk of long-term functional impairment. Pain management in hip fractured patients poses a challenge to the healthcare teams. Older adults are more vulnerable to opioid-associated side effect and it is primordial to minimize their exposure to opioids. Acetaminophen is associated with reduced opioid use so we need to focus on acetaminophen use in first-line analgesia. METHODS: We conducted a controlled before/after study to assess the ability of an audit and feedback (A&F) intervention built with nurses to improve the quality of perioperative pain management in older patients hospitalized for hip fracture in an orthogeriatric unit (experimental group) versus a conventional orthopedic unit (no A&F intervention). The primary endpoint was the percentage of patients who received 3 g/day of acetaminophen during the three postoperative days, before and after the A&F intervention. Secondary endpoints included nurses' adherence to medical prescriptions, clinical data associated with patients and finally factors associated with intervention. The significative level was set at 0.05 for statistical analysis. RESULTS: We studied data from 397 patients (mean age 89 years, 75% female). During the postoperative period, 16% of patients from the experimental group received 3 g/day of acetaminophen before the A&F intervention; the percentage reached 60% after the intervention. The likelihood of receiving 3 g/day of acetaminophen during the postoperative period and adhering to the medical prescription of acetaminophen were significantly increased in the experimental group as compared with the control group. The patient's functional status at discharge (assessed by Activities of Daily Living scores) was significantly better and the length of hospital stay significantly reduced after the A&F intervention. CONCLUSION: Our controlled before/after study showed that an A&F intervention significantly improved perioperative pain management in older adults hospitalized for hip fracture. Involving teams in continuous education programs appears crucial to improve the quality of pain management and ensure nurses' adherence to medical prescriptions.

Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells.

Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.

Fibroblast growth factor 21 alleviates acetaminophen induced acute liver injury by activating Sirt1 mediated autophagy.

BACKGROUND AND AIMS: Acetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved. METHODS: The ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level. RESULTS: FGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP. CONCLUSION: FGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.

Elevated temperature exacerbates pharmaceutical-induced oxidative stress in zebrafish (Danio rerio) larvae.

There is growing evidence that rising global temperatures resulting from climate change may exacerbate the toxic effect of pollutants and heterotherms, including fish, in which homestatic mechanisms are directly influenced by environmental temperature will be most affected. Pharmaceuticals discharged into the environment are potentially harmful to wildlife as many of their drug targets are conserved across divergent phyla. Oxidative stress (OS) is a major mechanism by which many pharmaceutical contaminants can induce toxicity but this has received little consideration in the context of effects in wildlife. Further, these mechanisms are relatively poorly understood, particularly regarding multiple stressor interactions. We used transgenic TG(EpRE:mCherry) zebrafish, developed in our laboratory for detecting OS, as our experimental model. We show that the oxidative effects of high concentrations of pharmaceuticals from three different therapeutic classes (paracetamol, diclofenac and doxorubicin) are increased at temperatures elevated by 2-5 °C above those for zebrafish standard husbandry and relevant to their current natural environment (and predicted under the IPCC 2023 scenarios for intermediate to very high greenhouse gas emissions). These OS responses were primarily seen in the pronephros, liver, and gastrointestinal tract. The increase in OS at the increased water temperature may have resulted from the elevated temperature acting as a direct additive physiological stressor to the OS imposed by the drugs and/or via the temperature increasing the chemicals oxidative effect. For paracetamol, it appeared that the elevated responses at the higher temperature of 33 °C were in part due to an increase in uptake of the drug. Our data illustrate that risk assessments for chemicals inducing OS in fish (and likely other heterotherms) should consider the influence of temperature to ensure environmental protection in future environments.