Search Results (630)

Pharmaceuticals are increasingly being detected in coastal ecosystems globally, but contamination and bioaccumulation levels are understudied in temporarily closed estuaries. In these systems, limited freshwater inputs and periodic closure may predispose them to pharmaceutical accumulation. We quantified in situ water column pharmaceutical levels at five sites in a temporarily closed model urban estuary (Zandvlei Estuary) in Cape Town, South Africa, that has been heavily anthropogenically modified. The results indicate an almost 100-fold greater concentration of pharmaceuticals in the estuary relative to False Bay, into which the estuary discharges, with acetaminophen (max: 2.531 µg/L) and sulfamethoxazole (max: 0.138 µg/L) being the primary pollutants. Acetaminophen was potentially bioaccumulative, while nevirapine, carbamazepine and sulfamethoxazole were bioaccumulated (BAF > 5000 L/kg) by sandprawns (Kraussillichirus kraussi), which are key coastal endobenthic ecosystem engineers in southern Africa. The assimilative capacity of temporarily closed estuarine environments may be adversely impacted by wastewater discharges that contain diverse pharmaceuticals, based upon the high bioaccumulation detected in key benthic engineers. Full article

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways. Full article

This study investigates the implications of sewage contamination in the coastal and riverine environments of Hout Bay, Cape Town, South Africa. Chemical analyses were applied to quantify the presence of pollutants such as pharmaceutical and personal care products (PPCPs) in sentinel marine organisms such as mussels, as well as microbial indicators of faecal contamination in river water and seawater, for estimating the extent of impact zones in the coastal environment of Hout Bay. This research investigated the persistent pharmaceuticals found in marine outfall wastewater effluent samples in Hout Bay, examining whether these substances were also detectable in marine biota, specifically focusing on Mytilus galloprovincialis mussels. The findings reveal significant levels of sewage-related pollutants in the sampled environments, with concentrations ranging from 32.74 to 43.02 ng/g dry weight (dw) for acetaminophen, up to 384.96 ng/g for bezafibrate, and as high as 338.56 ng/g for triclosan. These results highlight persistent PPCP contamination in marine organisms, with increasing concentrations observed over time, suggesting a rise in population and pharmaceutical use. Additionally, microbial analysis revealed high levels of E. coli in the Hout Bay River, particularly near stormwater from the Imizamo Yethu settlement, with counts exceeding 8.3 million cfu/100 mL. These findings underscore the significant impact of untreated sewage on the environment. This study concludes that current sewage treatment is insufficient to mitigate pollution, urging the implementation of more effective wastewater management practices and long-term monitoring of pharmaceutical levels in marine biota to protect both the environment and public health. Full article

The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients undergoing elective cardiac surgery with implementation of cardiopulmonary bypass had their serum isolated at baseline, 24 h, seven days, and three months postoperatively to assess serum concentrations of IGFALS and insulin growth factor 1 (IGF-1). Markers of perioperative injury included troponin I (TnI), high-mobility group box 1 (HMGB-1), and heat shock protein 60 (Hsp-60). Inflammatory status was assessed via interleukin-6 (IL-6) and interleukin-8 (IL-8). Additionally, we measured in vitro cytokine production to viral stimulation of whole blood and monocytes. Surrogates of neuronal distress included neurofilament light chain (NF-L), total tau (τ), phosphorylated tau at threonine 181 (τp181), and amyloid β40 and β42. Renal impairment was defined by RIFLE criteria. Cardiac dysfunction was denoted by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Serum IGFALS levels declined significantly after surgery and remained depressed even at 3 months. Administration of acetaminophen and acetylsalicylic acid differentiated IGFALS levels at the 24 h postoperatively. Serum IGFALS 24 h post-operatively correlated with production of cytokines by leukocytes after in vitro viral stimulation. Serum amyloid-β1-42 was significantly associated with IGFALS at baseline and 24 h post-surgery Patients discharged home had higher IGFALS levels at 28 days and 3 months than those discharged to healthcare facilities or who died. These findings suggest that IGFALS may serve as a prognostic biomarker for recovery trajectory and postoperative outcomes in cardiac surgery patients. Full article

Although it is more than a century since it was first marketed, acetaminophen remains one of the most popular analgesic agents. In addition, acetaminophen has recently been applied to multimodal analgesia in combination with non-steroidal anti-inflammatory drugs, and its consumption significantly increased during the pandemic of coronavirus disease 2019 as well as diclofenac and ibuprofen. However, the detailed mode of analgesic action of acetaminophen is still unclear. In the present study, we comprehensively discuss conventional, recognized, and postulated mechanisms of analgesic acetaminophen and highlight the current mechanistic concepts while comparing with diclofenac and ibuprofen. Acetaminophen inhibits cyclooxygenase with selectivity for cyclooxygenase-2, which is higher than that of ibuprofen but lower than that of diclofenac. In contrast to diclofenac and ibuprofen, however, anti-inflammatory effects of acetaminophen depend on the extracellular conditions of inflamed tissues. Since the discovery of cyclooxygenase-3 in the canine brain, acetaminophen had been hypothesized to inhibit such a cyclooxygenase-1 variant selectively. However, this hypothesis was abandoned because cyclooxygenase-3 was revealed not to be physiologically and clinically relevant to humans. Recent studies suggest that acetaminophen is deacetylated to 4-aminophenol in the liver and after crossing the blood–brain barrier, it is metabolically converted into N-(4-hydroxyphenyl)arachidonoylamide. This metabolite exhibits bioactivities by targeting transient receptor potential vanilloid 1 channel, cannabinoid receptor 1, Cav3.2 calcium channel, anandamide, and cyclooxygenase, mediating acetaminophen analgesia. These targets may be partly associated with diclofenac and ibuprofen. The perspective of acetaminophen as a prodrug will be crucial for a future strategy to develop analgesics with higher tolerability and activity. Full article

Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury (DILI) globally, which necessitates effective therapies. Gallic acid (GA), a naturally abundant polyphenol, possesses potent antioxidant and anti-inflammatory properties that may overcome the limitations of N-acetylcysteine (NAC), such as its narrow therapeutic window. This study systematically investigated the hepatoprotective effects and underlying molecular mechanisms of GA against APAP-induced acute liver injury (ALI). Mice received an intraperitoneal injection of APAP (300 mg/kg), followed by an oral administration of GA (50 or 100 mg/kg) or NAC (150 mg/kg) 1 h post-intoxication. Both GA and NAC significantly ameliorated hypertrophy and histopathological damage, as evidenced by reduced serum ALT/AST levels and inflammatory cytokines. TUNEL staining revealed a marked suppression of apoptotic and necrotic cell death, further supported by the downregulation of pro-apoptotic Bax and the upregulation of anti-apoptotic Bcl-2 mRNA expression. GA and NAC treatment restored hepatic glutathione (GSH) content, enhanced antioxidant enzyme gene expression, and reduced malondialdehyde (MDA) accumulation. Mechanistically, GA and NAC inhibited MAPK phosphorylation while activating AMPK signaling. Taken together, these findings demonstrate that GA mitigates APAP-induced ALI by modulating oxidative stress and inflammation through the regulation of MAPK/AMPK signaling proteins. Full article

Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the xCT/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the xCT/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury. Full article

Sulfotransferase (SULT) enzymes contribute significantly to drug metabolism in pediatric patients. The purpose of this study was to develop a PBPK model for acetaminophen (APAP) in pediatric populations that accounts for the ontogeny of SULT isozymes that play a critical role in APAP metabolism. PBPK modeling and simulation were performed using the Simcyp^® Simulator. The model incorporated the developmental ontogeny of three key hepatic SULT enzymes: SULT1A1, SULT1A3, and SULT2A1 using “best-fit” ontogeny equations for each isozyme as determined by nonlinear regression analysis of enzyme abundance versus age. PBPK model-simulated pharmacokinetic profiles for APAP captured observed clinical data for systemic exposure (Cmax, AUC) in neonates, infants, and children. SULTS accounted for ~60% APAP metabolism in neonates, with decreased contributions to infants and children. Model sensitivity analysis highlighted the potential for APAP metabolic DDIs, primarily through SULT1A1. The study demonstrates that the impact of SULT enzymes on drug metabolism is significant in neonates, which is an important clinical consideration for APAP. A PBPK model that incorporates SULT ontogeny has the potential to help inform dosing decisions in this special patient population. Full article

In this study, carbon adsorbents obtained from agricultural waste, i.e., walnut, hazelnut, and pistachio nutshells, were investigated for the removal of paracetamol (acetaminophen, 4-hydroxyacetanilide) (PAR) from aqueous solutions. Activated carbons (ACs) were produced via a two-step procedure. In the first step, the carbonization of nutshells was carried out at 600 °C, and in the second step, the chemical activation was carried out at 750 °C using alkaline activators, i.e., NaOH and KOH. For all of the ACs obtained and characterized, PAR adsorption kinetics, the adsorption at equilibrium, and the effects of the solution pH were investigated. All results obtained for each nutshell depend on the type of activating agent used. However, in the case of a given activator, there are differences resulting from the type of raw material. Kinetic and isothermal studies revealed that PAR adsorption follows the pseudo-second-order and the Langmuir models, respectively. The adsorption capacities of the ACs were very high and ranged from 332.2 to 437.8 mg/g. This study highlights the remarkable potential of nutshells as valuable and cost-effective precursors for the production of ACs that can effectively remove paracetamol from water. Full article

Oxidative stress, mitochondrial dysfunction, and inflammatory responses cause acute liver failure in most cases of acetaminophen (APAP) overdose. Tamarixetin (Trx), an antioxidant and anti-inflammatory flavonoid, has not yet been studied in models of APAP-induced hepatotoxicity. Trx was tested for its protective effects on APAP-induced liver injury in rats using biochemical, histopathological, and oxidative stress parameters. Three groups of 30 male Wistar rats were randomly assigned to the following groups: control, APAP + Saline, and APAP + Trx (3 mg/kg/day, intraperitoneally for 3 days). A single 300 mg/kg intraperitoneal APAP dose caused hepatotoxicity. ALT, MDA, GSH, HSP-70, and thioredoxin were measured in blood and liver tissues. Liver sections were histopathologically examined. APAP depleted hepatic GSH and Trx and increased serum ALT and MDA. Trx treatment significantly reduced ALT (201.2 → 105.1 U/L), MDA (5.5 → 3.4 nmol/mg), and the percentage of histologically damaged hepatocytes (58.5% → 9.5%), while restoring GSH and thioredoxin levels. Notably, HSP-70 expression exceeded that of APAP and control levels, suggesting the modulation of the stress response. The Trx group showed significant hepatoprotection histologically. Trx reduces APAP-induced hepatic damage, likely through antioxidant and anti-inflammatory mechanisms. These findings suggest that Trx may be a natural hepatoprotectant, warranting clinical trials. Full article

Water quality is essential for safeguarding human health and ensuring the stability of ecosystems. Nonetheless, the rising prevalence of emerging contaminants, particularly pharmaceutical compounds, has raised serious environmental concerns due to their bioactivity, widespread use, persistence, and potential toxicity. Among these, acetaminophen (paracetamol) is one of the most frequently detected pharmaceutical pollutants in aquatic environments. Among the various degradation strategies explored, biological methods, especially those involving white-rot fungi, have shown substantial promise owing to their production of ligninolytic enzymes capable of degrading complex pollutants. This study investigates the use of laccases from Ganoderma parvulum, covalently immobilized on chitosan microspheres, for acetaminophen degradation. The immobilization involved a 10% crosslinking agent, 60-min crosslinking time, and 10,000 U/L enzyme concentration, resulting in an immobilization efficiency of 123%, 203%, and 218%, respectively. The immobilized enzymes displayed enhanced stability across pH 3–8 and temperatures between 20 and 60 °C. Biodegradation assays achieved 97% acetaminophen removal within four hours. Nuclear Magnetic Resonance (¹H NMR and COSY) confirmed structural transformation. The enzymes also retained over 95% catalytic activity after multiple reuse cycles. These findings highlight the novel application of laccases as efficient and reusable biocatalysts for pharmaceutical pollutant removal, providing valuable insights into the mechanisms of enzymatic environmental remediation. Full article

Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated—developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS. Full article

Background: Caesarean section is considered one of the surgeries with the highest prevalence of postoperative pain, yet this is often underestimated and undertreated. This study was aimed at evaluating the prevalence and severity of postoperative pain, assessing which analgesic strategy is the most effective and identifying those risk factors associated with poorer analgesic results. Methods: A multi-centre observational study was conducted on 514 women undergoing elective caesarean section. The primary endpoints included postoperative pain severity at rest and with movement at 6 and 24 h. Results: The combination of intrathecal morphine and fentanyl with acetaminophen and Non Steroid Anti-inflammatory Drugs (NSAIDs) was associated with better pain control than any of the following treatments: intrathecal fentanyl with systemic acetaminophen and NSAIDs (2.49 ± 2.04 vs. 3.91 ± 2.75, ES = −0.610, p = 0.01), elastomeric pump at 6 h at rest (2.49 ± 2.04 vs. 4.10 ± 2.86, ES −0.733, p = 0.04) and with movement (4.44 ± 2.41 vs. 6.14 ± 3.08, ES −0.671, p = 0.01) or epidural analgesia (4.44 ± 2.41 vs. 5.65 ± 2.57, ES −0.496, p = 0.02). No risk factors predicting poorer postoperative analgesia were found. Conclusions: The prevalence of postoperative pain control after elective caesarean section is high. The best analgesic postoperative regimen includes intrathecal morphine together with fentanyl and systemic analgesics. No risk factors associated with poorer outcomes were found. Full article

Background: Osteoarthritis (OA) of the hip and knee is a common age-related degenerative disease characterized by joint pain, stiffness, and gait disturbances. This study investigated the influence of genetic polymorphisms in the OPRM1 (rs1799971) and COMT (rs4633, rs4680, rs4818, and rs6269) genes on the postoperative analgesic requirements in 195 diabetic and non-diabetic patients undergoing total hip or knee arthroplasty. Methods: The prospective study included all patients who were admitted between January and September 2020 and agreed to participate. Postoperative pain management was assessed based on acetaminophen, ketoprofen, and morphine consumption on the first and second postoperative day. Results: Multilevel regression analyses revealed a significant three-way interaction between diabetes, type of analgesic, and OPRM1rs1799971 polymorphism, indicating different analgesic dosing patterns in diabetic and non-diabetic patients. Two-way interactions between diabetes and COMT polymorphisms rs4633, rs4680, and rs6269 further influenced the analgesic requirements. No significant associations were found for COMT rs4818. The results show that diabetes and genetic factors significantly influence opioid requirements and pain perception. Conclusions: Given the complexity of pain management in diabetic patients, personalized analgesic strategies tailored to genetic and metabolic profiles could be useful in postoperative pain management and reducing opioid consumption. Full article

Shallow lakes are highly vulnerable to pollution due to their small water volume. Those that receive effluent from the drainfields of onsite wastewater treatment systems (septic tanks) may contain pharmaceuticals and personal care products (PPCPs) that escaped removal during treatment. This study examined the effects of seasonal rainfall variability on the assemblages and concentrations of fourteen PPCPs in two shallow lakes in West–Central Florida, USA: one surrounded by residents equipped with septic tanks and the other located within a nature preserve. Water samples were collected weekly during an 18-week interval from April to August 2021. Liquid chromatography–mass spectrometry analyses revealed the omnipresence of five PPCPs: theophylline, caffeine, cotinine, DEET, and testosterone, although acetaminophen, ibuprofen, and sulfamethoxazole were also common. Of all the PPCPs detected, theophylline, DEET, and acetaminophen concentrations were higher during the wet season in the septic tank-influenced lake, while caffeine, cotinine, and testosterone concentrations decreased. In the lake located in the nature preserve, theophylline, caffeine, and acetaminophen levels increased in the wet season. In contrast, cotinine, DEET, and testosterone levels decreased. Overall, more compounds were detected during the wet season, with highly hydrophobic PPCPs (fluoxetine, atorvastatin, and octocrylene) only present during this period. Full article