Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.

Background: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities. Aim: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats. Methods: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies. Results: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-ß1 levels, and marked elevation in the IgM levels. Conclusion: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.

Chronic Low Back Pain in Adults: Evaluation and Management.

Chronic low back pain, defined as lumbar pain persisting for 12 weeks or more, occurs in about 13% of U.S. adults. Patients with chronic low back pain should have a history and physical examination to identify red flags that may indicate serious conditions that warrant immediate intervention or yellow flags (i.e., psychological, environmental, and social factors) that indicate risk of disability. The examination should include an evaluation for radicular symptoms. Routine imaging is not recommended but is indicated when red flags are present, there is a neuromuscular deficit, or if pain does not resolve with conservative therapy. Patients should avoid bed rest. Nonpharmacologic treatment is first-line management and may include therapies with varying evidence of support, such as counseling, exercise therapy, spinal manipulation, massage, heat, dry needling, acupuncture, transcutaneous electrical nerve stimulation, and physical therapy. Pharmacologic interventions are second-line treatment. Nonsteroidal anti-inflammatory drugs are the initial medication of choice; duloxetine may also be beneficial. Evidence is inconclusive to recommend the use of benzodiazepines, muscle relaxants, antidepressants, corticosteroids, insomnia agents, anticonvulsants, cannabis, acetaminophen, or long-term opioids. Epidural corticosteroid injections are not recommended except for short-term symptom relief in patients with radicular pain. Most patients with chronic low back pain will not require surgery; evaluation for surgery may be considered in those with persistent functional disabilities and pain from progressive spinal stenosis, worsening spondylolisthesis, or herniated disk. Physicians should consider prevention of chronic low back pain when patients present with acute back pain. Screening tools are available to predict the progression from acute to chronic low back pain, and targeted treatment strategies are beneficial for preventing progression.

Changes in pharmacist's recommendations of over-the-counter treatments for the common cold during the COVID-19 pandemic.

BACKGROUND: The common cold is one of the most frequently occurring illnesses worldwide. The aim of this study was to determine which OTC anti-common cold medications were most often recommended by pharmacists and if the COVID-19 pandemic affected such recommendations. METHODS: Non-interventional, observational research trial using a self-developed questionnaire to collect data on pharmacists' recommendations for anti-common cold OTC treatment. The data were collected during the COVID-19 pandemic (December 2021-February 2022) in four large community network pharmacies in Lodz (Poland) and then compared with an analogue period of time before the pandemic (December 2019-February 2020). RESULTS: During COVID-19 pandemic there was a significant (p < 0.05) reduction in paracetamol, acetylsalicylic acid, metamizole magnesium, inosines, alpha-mimetics, mucolytics, homeopathics, and sore throat products and an increase in other tablets/capsules and add-on product recommendations. There was a significant relationship (p < 0.05, OR > 1) between the recommended frequency of paracetamol, inosines, sore throat products (each symptom), metamizole magnesium (headache, fever), acetylsalicylic acid (headache, fever, fatigue), NSAIDs, alpha-mimetics (headache, rhinorrhea), pseudoephedrine (rhinorrhea), homeopathics (headache), herbal products (fatigue), antihistamines (rhinorrhea, cough), and mucolytics (headache, fever, cough). CONCLUSIONS: Favorable prices (before COVID-19 pandemic) and reports on common NSAIDs side effects (beginning of the pandemic) led to high sale of paracetamol. Increased awareness of clinical effectiveness of some medications or their reduced availability influenced their limited recommendations.

Multi-omics reveals that 5-O-methylvisammioside prevention acute liver injury in mice by regulating the TNF/MAPK/NF-κB/arachidonic acid pathway.

BACKGROUND: The pathogenesis of acute liver injury (ALI) has been a pressing issue in the medical scientific community. We previously found that 5-O-methylvisammioside (MeV) from Saposhnikovia divaricata (Turcz.) Schischk has excellent anti-inflammatory properties. However, the mechanism by which MeV protects against ALI still needs to be deeply investigated. PURPOSE: In the present study, we established an acetaminophen (APAP) -induced ALI mouse model and pre-protected the mice with MeV. METHODS & RESULTS: Our findings indicate that MeV (5 and 10 mg/kg) lowered the blood levels of alanine aminotransferase and aspartate aminotransferase and reduced the infiltration of inflammatory cells in the liver. MeV initially showed an inhibitory effect on ALI. We then analyzed the molecular mechanisms underlying the effects of MeV by transcriptomic and metabolomic analyzes. Through transcriptomic analysis, we identified 4675 differentially expressed genes between the APAP+MeV group and the APAP-induced ALI group, which were mainly enriched in the MAPK pathway, the TNF pathway, and the NF-κB pathway. Through metabolomic analysis, we found that 249 metabolites in the liver were differentially regulated between the APAP+MeV group and the APAP- induced ALI group, which were mainly enriched in the arachidonic acid pathway. The mRNA expression levels of key genes (encoding TNF-α, p38, AP-1, RelB, IL-1ß, and Ptges), as determined by RT-PCR analysis, were consistent with the RNA-seq data. The ELISA results indicate that MeV markedly decreased the serum levels of TNF-α and IL-1ß in mice. Finally, the key proteins in the NF-κB and MAPK pathways were examined using immunoblotting. The results showed that MeV decreased IκB-α phosphorylation and inhibited the nuclear translocation of NF-κB. In addition, MeV reduced the hepatic inflammatory burst mainly by inhibiting the phosphorylation of p38 and JNK in the MAPK pathway. CONCLUSION: The present study demonstrated (i) that MeV could ameliorate APAP-induced ALI by inhibiting arachidonic acid metabolism and the TNF, MAPK, and NF-κB pathways, and (ii) that MeV is a promising drug candidate for the prevention of ALI.

Shoulder pain management strategies and early functional outcome after arthroscopic rotator cuff tear repair. A randomized controlled study.

BACKGROUND: The management of acute postoperative pain after rotator cuff surgery can be challenging. To our knowledge, there are no data available in the literature correlating satisfactory pain control with improvement in terms of function. The purposes of the present study were to evaluate: 1) pain pattern after arthroscopic rotator cuff repair in patients operated with two different techniques (transosseous vs transosseous equivalent); 2) safety/efficacy of three different pharmacological pain control strategies; 3) possible relationship between a correct shoulder pain management protocol in the early post-operative period and patients' functional improvement. METHODS: 114 patients underwent rotator cuff tear repair, either with a Transosseus or a Transosseus equivalent technique. 62 (54%) were male and 52 (46%) were female. The average age was 59 ± 9 years. They were randomly assigned into three different pain management protocols: Paracetamol as needed (max 3 tablets/day) for 1 week (Protocol A), Paracetamol + Codein 1 tablet three times per day for 7 days (Protocol B), or Paracetamol + Ibuprofen 1 tablet two times per day for 7 days (Protocol C). Immediate passive mobilization of the operated shoulder was allowed. VAS and Passive Flexion values were recorded at 7 (T1), 15 (T2) and 30 (T3) days post-surgery. DASH values were recorded at 90 days post-surgery. All patients were asked to register any kind of signs/symptoms that may appear during drug assumption according to each pain management protocols. RESULTS: All the pain management protocols administered were well tolerated by all the study population, and no adverse signs/symptoms were highlighted during drug assumption. Pain pattern: in both surgical techniques, patients within Protocol A were associated with worst results in terms of mean VAS at each time point examined when compared to Protocol B and C (p < 0,05). In patients within Protocol A, no statistically significant differences were found at each point time examined comparing the two surgical techniques, with the exception of T2, where the TO was associated with an higher VAS value than TOE (p < 0.05). No differences were highlighted in Protocol B and C when comparing the values between two surgical techniques. ROM: in both surgical techniques, patients within Protocol A were associated with worst results in terms of mean PROM at each time point examined when compared to Protocol B and C (p < 0,05). In the TO group, patients within Protocol B had better PROM values at T1 (p < 0,05) and T2 (p < 0,05) compared to Protocol C, but no differences were highlighted at T3. In the TOE group, no statistically significant differences were found between patients within Protocol B and C at each time point examined. DASH: In the TO group, no statistically significant differences were found regarding the DASH values comparing Protocol B vs Protocol C, but they were highlighted comparing the values between Protocol A and Protocol B (p < 0,05), and between Protocol A and Protocol C (p < 0,05). Similar results were recorded in the TOE group. CONCLUSION: Post-operative pain is influenced by the surgical technique used being transosseous more painful in the first 15 days after surgery. Oral anti-inflammatory drugs are a feasible strategy to appropriately control post-operative pain. An association between Paracetamol and either Codein or Ibuprofen can lead to better outcomes in terms of VAS reduction and early recovery of passive ROM.

Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Protective Effect of Black Seed and Lettuce Oils Against Paracetamol-Induced Hepatotoxicity in Rats.

<b>Background and Objective:</b> The liver is one of the organs that play an essential role in the human body, including supporting metabolism, immune functions, digestive system, detoxification, storage of vitamins and other functions. This investigation aimed to study the protective effects of black seed and lettuce oil against hepatotoxicity as induced by paracetamol in experimental rats. <b>Materials and Methods:</b> Twenty male Sprague-Dawley albino rats weighing 150±5 g were divided randomly into four groups (5 rats each) and distributed as follows; 1st group was controlled negative (C -ve group), 2nd group controlled positive (orally administered with 500 mg/kg b.wt., paracetamol), 3rd and 4th groups were orally administered with black seed oil and lettuce oil at a dose of 1 mL/kg b.wt., each) as a preventive dose. All rats were sacrificed and blood was collected for biochemical analysis and then statistically analyzed. <b>Results:</b> The rat administered with black seed and lettuce oils enhanced body weight gain, food intake and feed efficiency ratio. Moreover, exhibited a significant reduction in the liver enzymes AST, ALT, ALP and TBIL. Meanwhile, black seed and lettuce oils significantly improved kidney functions, lipid profiles and some immune biomarkers including creatine kinase (CK), Creatine Kinase-MB (CK-MB) and Lactate Dehydrogenase (LDH). <b>Conclusion:</b> This study revealed that the oils of black seed (<i>Nigella sativa</i>) and lettuce (<i>Lactuca sativa</i>) have a protective role in improving body weight gain, food intake, feed efficiency ratio, liver enzymes, kidney functions, lipid profiles and some immune biomarkers against paracetamol-induced hepatotoxicity in experimental rats.

Local anaesthesia for pain control in first trimester surgical abortion.

BACKGROUND: Abortions prior to 14 weeks are among the most common outpatient surgical procedures performed on people capable of becoming pregnant. Various methods have been used to control pain; however, many people still experience pain with the procedure. OBJECTIVES: To evaluate the benefits and harms of local anaesthesia given for pain control during surgical abortion at less than 14 weeks' gestation. SEARCH METHODS: We searched CENTRAL (Ovid EBM Reviews), MEDLINE (Ovid), Embase, POPLINE, and Google Scholar to December 2022 for randomized controlled trials of pain control in surgical abortion at less than 14 weeks' gestation using suction aspiration. We searched the reference lists of related reviews and articles. SELECTION CRITERIA: We selected effectiveness and comparative effectiveness randomized controlled trials that studied local anaesthesia with common local anaesthetics and administration routes given for pain control in surgical abortion at less than 14 weeks' gestation using uterine aspiration. Outcomes included intraoperative pain, patient satisfaction, and adverse events. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We computed mean differences (MD) with 95% confidence intervals (CI) for continuous variables reporting a mean. We assessed the certainty of evidence using GRADE. MAIN RESULTS: Thirteen studies with 1992 participants met the inclusion criteria. Due to heterogeneity of interventions, we could not pool more than two studies for any outcome. We used 13 mm improvement on a visual/verbal analogue scale to indicate a clinically meaningful difference in pain with surgical abortion (pain with dilation, aspiration, or during procedure). Based on type of pain control, we divided studies into three groups. Paracervical block (PCB) effectiveness trials A 20 mL 1% lidocaine PCB reduced pain with dilation (MD -37.00, 95% CI -45.64 to -28.36), and aspiration (MD -26.00, 95% CI -33.48 to -18.52) compared to a sham PCB (1 RCT, 120 participants; high-certainty evidence). A PCB with 14 mL of 1% chloroprocaine resulted in a slight reduction in pain with aspiration compared to a PCB with normal saline injected at two or four sites (MD -1.50, 95% CI -2.45 to -0.55; 1 RCT, 79 participants; high-certainty evidence). PCB comparative effectiveness trials An ultracaine PCB probably results in little to no clinically meaningful difference in pain during procedure compared to topical cervical lidocaine spray (median 1 point higher, interquartile range (IQR) 0 to 3; P < 0.001; 1 RCT, 48 participants; moderate-certainty evidence). A 1000 mg dose of intravenous paracetamol probably does not decrease pain as much as ultracaine PCB during procedure (median 2 points higher, IQR 1 to 3; P < 0.001; 1 RCT, 46 participants; moderate-certainty evidence). Various local anaesthetics in PCB comparative effectiveness trials A 10 mL buffered 2% lidocaine PCB probably does not result in a clinically meaningful difference in pain with dilation compared to a plain lidocaine PCB (MD -0.80, 95% CI -0.89 to -0.71; 1 RCT, 167 participants; moderate-certainty evidence). A buffered lidocaine PCB probably does not result in a clinically meaningful difference in pain with aspiration compared to plain lidocaine PCB (MD -0.57, 95% CI -1.01 to -0.06; 2 RCTs, 291 participants; moderate-certainty evidence). Non-PCB local anaesthesia or PCB technique effectiveness trials PCB: waiting versus no waiting Waiting three to five minutes between 1% lidocaine PCB injection and dilation probably does not result in a clinically meaningful difference in pain with dilation compared to not waiting (MD -0.70, 95% CI -1.23 to -0.17; 2 RCTs, 357 participants; moderate-certainty evidence). Topical cervical analgesia Topical 10 mL 2% lignocaine gel probably does not result in a clinically meaningful difference in pain with aspiration compared to KY Jelly (MD -0.87, 95% CI -1.60 to -0.14; 1 RCT, 131 participants; moderate-certainty evidence). In participants who also received a PCB, 20 mg topical cervical lidocaine spray probably does not result in a clinically meaningful difference in pain during the procedure compared to two pumps of normal saline spray (median -1 point, IQR -2 to -1; P < 0.001; 1 RCT, 55 participants; moderate-certainty evidence). Intravenous paracetamol 1000 mg compared to two pumps of cervical lidocaine spray probably does not results in a clinically meaningful difference in pain procedure (median 1 point, IQR -2 to 2; P < 0.001; 1 RCT, 48 participants; low-certainty evidence). Non-PCB local anaesthesia or PCB technique comparative effectiveness trials Depth of PCB The evidence suggests that a 3-cm deep PCB probably does not result in a clinically meaningful difference in pain with aspiration compared to a 1.5-cm deep PCB (MD -1.00, 95% CI -1.09 to -0.91; 2 RCTs, 229 participants; low-certainty evidence). PCB: four sites versus two sites A two-site (4-8 o'clock) 20 mL 1% lidocaine PCB does not result in a clinically meaningful difference in pain with dilation compared to a four-site (2-4-8-10 o'clock) PCB (MD 8.60, 95% CI 0.69 to 16.51; 1 RCT, 163 participants; high-certainty evidence). Overall, participants reported moderately high satisfaction with pain control and studies reported few adverse events. AUTHORS' CONCLUSIONS: Evidence from this updated review indicates that a 20 mL 1% plain lidocaine PCB decreases pain during an abortion procedure. Evidence supports forgoing buffering lidocaine and a wait time between PCB injection and cervical dilation. A 1.5-cm deep injection as opposed to a 3-cm deep injection is sufficient. A two-site PCB injection as opposed to a four-site injection has similar effectiveness. Topical cervical anaesthesia (10 mL 2% lignocaine gel or 20 mg topical cervical lidocaine spray) as compared to placebo did not decrease pain based on moderate-certainty evidence, but then when compared to PCB, pain control was similar. Due to this inconsistency in evidence regarding the effectiveness of topical anaesthesia, its routine use is presently not supported. This review did not include studies of pain management with conscious sedation but, based on the results of our prior Cochrane review and the 2022 WHO guidelines, we recommend that the option of combination of pain management using conscious sedation plus PCB and non-steroidal anti-inflammatory drugs should be offered where conscious sedation is available as it further decreases pain.

Does interferential current provide additional benefit to orthopedic rehabilitation for the patients with proximal humeral fractures? A randomized controlled study.

BACKGROUND: Approximately 80% of all proximal humeral fractures (PHFs) are non-displaced or minimally displaced fractures, which can be treated with conservative treatment. This study investigated the effect of interferential current (IFC) added to orthopedic rehabilitation on shoulder function, pain, and disability in patients with PHF. METHODS: This study was a prospective, double-blind, randomized, placebo-controlled conducted in physical medicine and rehabilitation outpatient clinic. Thirty-five patients were randomly separated into the IFC group (n = 18) and the sham group (n = 17). The orthopedic rehabilitation program was applied to all patients by the same physiotherapist three times a week for four weeks. Patients in the IFC group received the intervention for 20 minutes 3 times a week before the exercise. The same pads were performed for the sham group, but no electrical stimulation was applied. Constant-Murley score (CMS) for shoulder function, visual analog scale (VAS) activity pain, disabilities of the arm, shoulder, and hand (DASH) score, and paracetamol intake were recorded post-treatment, at 6 weeks and 18 weeks post-treatment. RESULTS: The demographic and fracture characteristics were not different between the groups. Significant differences were observed in the IFC and sham group in intragroup comparisons of total CMS, VAS activity pain, DASH score, and paracetamol intake over time (p < 0.001). Significant improvement over time was valid for all pairwise comparisons in both groups. However, no significant differences were detected between the IFC and sham group. CONCLUSION: IFC added to orthopedic rehabilitation could not appear to be an electrotherapy modality that could potentially benefit shoulder function and disability in patients with PHF.

Ameliorative Effect of Macadamia Nut Protein Peptides on Acetaminophen-Induced Acute Liver Injury in Mice.

This study aims to examine the ameliorative effect of macadamia nut protein peptides (MPP) on acetaminophen (APAP)-induced liver injury (AILI) in mice, and develop a new strategy for identifying hepatoprotective functional foods. The molecular weight distribution and amino acid composition of MPP were first studied. Forty mice were then randomized into four groups: control group (CON), APAP model group, APAP+MPP low-dose group (APAP+L-MPP), and APAP+MPP high-dose group (APAP+H-MPP). The APAP+L-MPP (320 mg/kg per day) and APAP+H-MPP (640 mg/kg per day) groups received continuous MPP gavage for 2 weeks. A 12 h of APAP (200 mg/kg) gavage resulted in liver damage. Pathological alterations, antioxidant index levels, expression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB), and associated inflammatory factors were determined for each treatment group. The results revealed that the total amino acid content of MPP was 39.58 g/100 g, with Glu, Arg, Asp, Leu, Tyr, and Gly being the major amino acids. The molecular weight range of 0-1000 Da accounted for 73.54%, and 0-500 Da accounted for 62.84% of MPP. MPP ameliorated the pathological morphology and reduced the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase of AILI in mice. MPP significantly increased the activities of superoxide dismutase and glutathione peroxidase in the liver compared with the APAP group. MPP inhibited the expression of TLR4, NF-κB, interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) genes in AILI mice. MPP also inhibited the expression levels of inflammatory factors (TNF-α and IL-6). Our study concludes that MPP alleviates AILI in mice by enhancing antioxidant capacity and inhibiting TLR4/NF-κB pathway-related gene activation.

The Modulation of Phospho-Extracellular Signal-Regulated Kinase and Phospho-Protein Kinase B Signaling Pathways plus Activity of Macrophage-Stimulating Protein Contribute to the Protective Effect of Stachydrine on Acetaminophen-Induced Liver Injury.

Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.

A comparison of the mixed and sequential use of acetaminophen and dexketoprofen in painful vaso-occlusive crises.

PURPOSE: Opioids are widely used to treat painful vaso-occlusive crises (VOC) in sickle cell disease (SCD). However, due to opioids' significant adverse effect profiles, the search for alternative therapies continues from the past to the present. The study aimed to investigate the efficacy of acetaminophen and dexketoprofen in the treatment of painful VOC. METHODS: This study is a single-center, prospective, non-randomized, single-blinded, controlled study. The study comprised two groups: the first administered acetaminophen and dexketoprofen mixed group, while the second received them sequential group. Opioids were used in patients with persistent pain despite these analgesics. Demographic and laboratory information, pain scores, opioid requirement, dose amount, side effects, and length of hospital stay of the patients were recorded. RESULTS: The study comprised 56 (100%) patients with painful VOC, 29 (51.8%) from the mixed group, and 27 (48.2%) from the sequential group. Opioid use was seen in 16 (55.2%) patients in the mixed group and 21 (77.8%) patients in the sequential group (p = 0.074). The median amount of opioid used was significantly lower in the mixed group than in the sequential group (p < 0.001). Also, the median length of hospital stay was significantly lower in the mixed group than in the sequential group (p < 0.001). CONCLUSION: Our study suggests that administering acetaminophen and dexketoprofen in the mix for the treatment of painful VOC in patients with SCD may be a more efficient approach compared to sequential administration. This approach appears to reduce opioid usage and shorten hospital stays.

Network pharmacology and experimental validation of effects of total saponins extracted from Abrus cantoniensis Hance on acetaminophen-induced liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Abrus cantoniensis Hance (AC), an abrus cantoniensis herb, is a Chinese medicinal herb used for the treatment of hepatitis. Total saponins extracted from AC (ACS) are a compound of triterpenoid saponins, which have protective properties against both chemical and immunological liver injuries. Nevertheless, ACS has not been proven to have an influence on drug-induced liver injury (DILI). AIM OF THE STUDY: This study used network pharmacology and experiments to investigate the effects of ACS on acetaminophen (APAP)-induced liver injury. MATERIALS AND METHODS: The targets associated with ACS and DILI were obtained from online databases. Cytoscape software was utilized to construct a "compound-target" network. In addition, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to analyze the related signaling pathways impacted by ACS. AutoDock Vina was utilized to evaluate the binding affinity between bioactive compounds and the key targets. To validate the findings of network pharmacology, in vitro and in vivo experiments were conducted. Cell viability assay, transaminase activity detection, immunofluorescence assay, immunohistochemistry staining, RT-qPCR, and western blotting were utilized to explore the effects of ACS. RESULTS: 25 active compounds and 217 targets of ACS were screened, of which 94 common targets were considered as potential targets for ACS treating APAP-induced liver injury. GO and KEGG analyses showed that the effects of ACS exert their effects on liver injury through suppressing inflammatory response, oxidative stress, and apoptosis. Molecular docking results demonstrated that core active compounds of ACS were successfully docked to core targets such as CASP3, BCL2L1, MAPK8, MAPK14, PTGS2, and NOS2. In vitro experiments showed that ACS effectively attenuated APAP-induced damage through suppressing transaminase activity and attenuating apoptosis. Furthermore, in vivo studies demonstrated that ACS alleviated pathological changes in APAP-treated mice and attenuated inflammatory response. Additionally, ACS downregulated the expression of iNOS, COX2, and Caspase-3, and upregulated the expression of Bcl-2. ACS also suppressed the MAPK signaling pathway. CONCLUSIONS: This study demonstrated that ACS is a hepatoprotective drug through the combination of network pharmacology and in vitro and in vivo experiments. The findings reveal that ACS effectively attenuate APAP-induced oxidative stress, apoptosis, and inflammation through inhibiting the MAPK signaling pathway. Consequently, this research offers novel evidence supporting the potential preventive efficacy of ACS.

Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.

Treatment of rheumatic musculoskeletal disorders.

Non-medicinal therapies with water, salts, exercise, massage, supportive devices, and electricity have been used for centuries and continue to be of benefit for some people with musculoskeletal disorders. Historical texts refer to the two electuaries mithridatium and theriaca as early therapeutic attempts of man to provide relief of musculoskeletal symptoms and attempt disease cures. For over 200 years, morphine-derived products have been used for musculoskeletal pain. The development of acetyl salicylic acid was a major breakthrough in joint pain management. This was followed by the introduction of nonsteroidal anti-inflammatory agents, paracetamol, and the use of corticosteroids. The gold-based compounds were the initial disease-modifying drugs and have been followed by the highly successful biologics agents. The basic objectives of musculoskeletal pain management include: reduction or elimination of joint pain; improvement or restoration of joint function and mobility; improvement of muscle strength to protect cartilage, ligaments, and joint capsule; prevention and reduction of damage to joint cartilage and supporting structures.

Allicin and Omega-3 fatty acids attenuates acetaminophen mediated renal toxicity and modulates oxidative stress, and cell apoptosis in rats.

Acetaminophen (APAP), a widely used medication known for its pain-relieving and fever-reducing effects, can cause kidney failure if taken in excess. To investigate the potential protective effects of allicin (ALC) and/or omega-3 fatty acids (O3FA) against acetaminophen-induced kidney damage, a study was conducted using 49 rats divided into seven groups. The control group was given saline, while the other groups received ALC, O3FA, APAP, ALC + APAP, O3FA + APAP, or ALC + O3FA + APAP. After administering APAP, the rats showed decreased levels of total protein and albumin in their blood, along with increased levels of creatinine and urea. The concentration of reduced glutathione (GSH), as well as the activity of superoxide dismutase (SOD) and catalase (CAT), decreased, while the level of malondialdehyde (MDA) in the renal tissues increased. The activation of caspase-3 and HSP70 also suggested an impact on kidney histopathology. Overall, the study found that ALC and/or O3FA may have a protective impact against acetaminophen-induced kidney damage through their anti-inflammatory, anti-apoptotic, and antioxidant defense systems.

Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: An integrated strategy of network pharmacology, metabolomics and transcriptomics.

BACKGROUND: Drug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PURPOSE: This study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. METHODS: We employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. RESULTS: Network pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1ß, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. CONCLUSION: QWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.

Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.

High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.

Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.