Analgesic Acetaminophen Research Articles

The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Size controlled synthesis of hydrous TiO2 spheres by a thiol structure directing agent and its application in photocatalysis and efficient DSSC cells

In this work, hydrated TiO2 spheres (HTS) of the submicron order have been developed. Normally, the group of amines, such as dodecylamine, hexadecylamine, methylamine, and NH3, had been the main structure-directing agents (SDAs) used in the sol–gel process to obtain monodisperse hydrated TiO2 spheres. Even though progress has been made in the synthesis of HTS, it is crucial to include new SDAs capable of synthesizing monodisperse HTS with improved or new properties for practical applications. In this work, for the first time we demonstrate that a thiol, 3-mercaptopropionic acid (MPA), can be used as an effective SDA to synthesize monodisperse hydrous TiO2 spheres with a controllable particle diameter between 150 to 950 nm. Experimental preparation parameters such as Ti concentration, [MPA]/[Ti] and [Water]/[Ti] molar ratio in the precursor solution (Titanium (IV) butoxide—MPA—ethanol—water) were thoroughly optimized to get both high yield and high monodispersity. Remarkably, a wide range in the [Water]/[Ti] molar ratio, 17 to 118, was achieved, which is much wider than the typical Rw range of the amines group of 2 to 16, thus giving more control for choosing the HTS final size. The controlled growth of hydrated TiO2 nanospheres was explained according to the LaMer and DVLO theory. To demonstrate the applicability of the HTS synthesized using MPA as SDA, the development of efficient dye-sensitized solar cells getting an energy conversion greater than 9% as well as of an effective photocatalytic degradation process of the analgesic acetaminophen under concentrated solar radiation was conducted.

Metabolomic-Based Comparison of Daphnia magna and Japanese Medaka Responses After Exposure to Acetaminophen, Diclofenac, and Ibuprofen.

Pharmaceuticals are found in aquatic environments due to their widespread use and environmental persistence. To date, a range of impairments to aquatic organisms has been reported with exposure to pharmaceuticals; however, further comparisons of their impacts across different species on the molecular level are needed. In the present study, the crustacean Daphnia magna and the freshwater fish Japanese medaka, common model organisms in aquatic toxicity, were exposed for 48 h to the common analgesics acetaminophen (ACT), diclofenac (DCF), and ibuprofen (IBU) at sublethal concentrations. A targeted metabolomic-based approach, using liquid chromatography-tandem mass spectrometry to quantify polar metabolites from individual daphnids and fish was used. Multivariate analyses and metabolite changes identified differences in the metabolite profile for D. magna and medaka, with more metabolic perturbations for D. magna. Pathway analyses uncovered disruptions to pathways associated with protein synthesis and amino acid metabolism with D. magna exposure to all three analgesics. In contrast, medaka exposure resulted in disrupted pathways with DCF only and not ACT and IBU. Overall, the observed perturbations in the biochemistry of both organisms were different and consistent with assessments using other endpoints reporting that D. magna is more sensitive to pollutants than medaka in short-term studies. Our findings demonstrate that molecular-level responses to analgesic exposure can reflect observations of other endpoints, such as immobilization and mortality. Thus, environmental metabolomics can be a valuable tool for selecting sentinel species for the biomonitoring of freshwater ecosystems while also uncovering mechanistic information. Environ Toxicol Chem 2024;43:1339-1351. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Emerging trends on nanomaterial-based simultaneous electrochemical sensing of dopamine and acetaminophen

Recent years have witnessed significant developments in electrochemical sensing, especially voltammetric techniques, which are known for providing flexible platforms for the simultaneous measurement of the analgesic acetaminophen (AC) and the neurotransmitter dopamine (DA). The most recent advancements and trends in electrochemical methods for the simultaneous detection of these two analytes are thoroughly reviewed in this paper. The different novel electrode materials, viz. nanostructures, and several surface modifications used to improve the sensitivity, selectivity, and stability of sensors that target the electrochemistry of acetaminophen and dopamine, have been carried out in studies published in the last decade. A wide range of voltammetric techniques are covered in this investigation, such as square wave voltammetry, differential pulse voltammetry, and cyclic voltammetry. The review also critically examines the drawbacks and restrictions of the existing approaches, which range from problems with selectivity in intricate matrices to the requirement for in-vivo applications and real-time monitoring in terms of diagnostics. The pursuit of multifunctional sensors, integration of advanced nanomaterials, and standardization of experimental conditions are identified as critical research gaps. The study concludes with some notions about potential future developments, highlighting the possible influence of current trends on the advancement of electrochemical sensors for the simultaneous measurement of dopamine and acetaminophen. It also suggests future directions for ongoing research and how the exploration of unexplored areas can be attended to develop highly sensitive, selective, and cost-effective electrochemical sensors.

Cobalt and zinc imidazolate encapsulated in reduced graphene oxide and the derived nitrogen-enriched carbon frameworks (CoNC@rGO) for electrochemically sensing acetaminophen (APAP)

Electrochemical detection of the analgesic acetaminophen (APAP) was carried out using a composite of cobalt and zinc imidazolate frameworks and graphene oxie (Co/ZnZIF@GO). Co/ZnZIF@GO was thermally reduced to create cobalt/nitrogen-enriched carbon and reduced graphene oxide (CoNC@rGO), which greatly facilitated the current response for APAP sensing. The mesoporosity of NC cubes embedded in rGO sheets and the dispersity of Co nanoparticles were manipulated by the carbonization temperature. Electroanalysis and Raman spectra revealed that the reversible conversion of phenolic hydroxyl to ketone in the doubly chelated APAP on surface Co sites accounted for the faradaic current of APAP oxidation. CoNC@rGO(800), synthesized at 800 °C under a N2 atmosphere, with an optimal metal ratio of Co0.5Zn0.5 and 50 % GO loading maximized electrode sensitivity. This resulted in a high sensitivity (0.598 μA μM−1) and a low detection limit (0.067 μM) in the range of 0.5–50 μM. Through the differential pulse voltammetry technique (DPV), the synthesized sensor exhibited excellent reproducibility, selectivity, and recovery for detecting APAP in various real-world water samples.

Domestic Waste and Wastewaters as Potential Sources of Pharmaceuticals in Nestling White Storks (Ciconia ciconia).

Information on the exposure of wild birds to pharmaceuticals from wastewater and urban refuse is scarce despite the enormous amount of drugs consumed and discarded by human populations. We tested for the presence of a battery of antibiotics, NSAIDs, and analgesics in the blood of white stork (Ciconia ciconia) nestlings in the vicinity of urban waste dumps and contaminated rivers in Madrid, central Spain. We also carried out a literature review on the occurrence and concentration of the tested compounds in other wild bird species to further evaluate possible shared exposure routes with white storks. The presence of two pharmaceutical drugs (the analgesic acetaminophen and the antibiotic marbofloxacin) out of fourteen analysed in the blood of nestlings was confirmed in 15% of individuals (n = 20) and in 30% of the nests (n = 10). The apparently low occurrence and concentration (acetaminophen: 9.45 ng mL-1; marbofloxacin: 7.21 ng mL-1) in nestlings from different nests suggests the uptake through food acquired in rubbish dumps rather than through contaminated flowing water provided by parents to offspring. As with other synthetic materials, different administration forms (tablets, capsules, and gels) of acetaminophen discarded in household waste could be accidentally ingested when parent storks forage on rubbish to provide meat scraps to their nestlings. The presence of the fluoroquinolone marbofloxacin, exclusively used in veterinary medicine, suggests exposure via consumption of meat residues of treated animals for human consumption found in rubbish dumps, as documented previously at higher concentrations in vultures consuming entire carcasses of large livestock. Control measures and ecopharmacovigilance frameworks are needed to minimize the release of pharmaceutical compounds from the human population into the environment.

Evaluation of Pharmaceuticals for DNA Damage in the Chicken Egg Genotoxicity Assay (CEGA).

DNA damage is an established initiating event in the mutagenicity and carcinogenicity of genotoxic chemicals. Accordingly, assessment of this endpoint is critical for chemicals which are being developed for use in humans. To assess the ability of the Chicken Egg Genotoxicity Assay (CEGA) to detect genotoxic pharmaceuticals, a set of 23 compounds with different pharmacological and reported genotoxic effects was tested for the potential to produce nuclear DNA adducts and strand breaks in the embryo-fetal livers using the 32P-nucleotide postlabeling (NPL) and comet assays, respectively. Due to high toxicity, two aneugens, colchicine and vinblastine, and an autophagy inhibitor, hydroxychloroquine, could not be evaluated. Out of the 20 remaining pharmaceuticals, 10 including estrogen modulators, diethylstilbestrol and tamoxifen, antineoplastics cyclophosphamide, etoposide, and mitomycin C, antifungal griseofulvin, local anesthetics lidocaine and prilocaine, and antihistamines diphenhydramine and doxylamine, yielded clear positive outcomes in at least one of the assays. The antihypertensive vasodilator hydralazine and antineoplastics streptozotocin and teniposide, produced only DNA strand breaks, which were not dose-dependent, and thus, the results with these 3 pharmaceuticals were considered equivocal. No DNA damage was detected for 7 compounds, including the purine antagonist 6-thioguanine, antipyretic analgesics acetaminophen and phenacetin, antibiotic ciprofloxacin, antilipidemic clofibrate, anti-inflammatory ibuprofen, and sedative phenobarbital. However, low solubility of these compounds limited dosages tested in CEGA. Overall, results in CEGA were largely in concordance with the outcomes in other systems in vitro and in vivo, indicating that CEGA provides reliable detection of DNA damaging activity of genotoxic compounds. Further evaluations with a broader set of compounds would support this conclusion.

The Effect of Pre-Emptive Analgesia on the Postoperative Pain in Pediatric Otolaryngology: A Randomized, Controlled Trial.

The aim of this randomized, controlled trial was to determine whether children undergoing otolaryngological procedures (adenoidectomy, adenotonsillotomy, or tonsillectomy) benefit from pre-emptive analgesia in the postoperative period. Methods: Fifty-five children were assessed for eligibility for the research. Four children refused to participate during the first stage of the study, leaving fifty-one (n = 51) to be randomly assigned either to receive pre-emptive analgesic acetaminophen (15 mg/kg; n = 26) or a placebo (n = 25) in addition to midazolam (0.5 mg/kg) as premedication. All children were anesthetized with sevoflurane, propofol (2–4 mg/kg), and fentanyl (2 mcg/kg). Postoperative pain was assessed using the Visual Analogue Scale (VAS), the Wong–Baker Faces Pain Rating Scale, and the Face, Legs, Activity, Cry, and Consolability (FLACC) scale. The postoperative pain was measured 1, 2, 4, and 6 h after the surgery. Results: The clinical trial reported a statistically significant correlation between administering pre-emptive analgesia (acetaminophen) and reducing pain in children after otolaryngological procedures compared to placebo. The ratio of boys to girls and age were similar among the groups (p > 0.05), so the groups of children were not divided by gender or age. Conclusions: Standard pre-emptive analgesia reduced the severity of pain in the postoperative period after otolaryngological procedures in children. Acetaminophen given before surgery reduces postoperative pain in children undergoing otolaryngological procedures.

Occurrence and accumulation of pharmaceutical products in water and biota of urban lowland rivers

We evaluated the distribution of eleven groups of pharmaceutically active compounds (PhACs) in surface waters and biota of different trophic levels, in five sites of two lowland urban rivers in Argentine. Twenty-nine out of 39 PhACs and two metabolites were detected in at least one water sample (2–9622 ng/L), eleven detected in biofilms (1–179 ng/g d.w.) and eight in the macrophyte Lemna gibba (4–112 ng/g d.w). The two more polluted sites had a similar distribution of the main groups of compounds. In surface waters, the largest concentrations were for the analgesic acetaminophen (9622 ng/L), the antibiotic sulfamethoxazole (326 ng/L), the antihypertensive valsartan (963 ng/L), the β-blocking agent atenolol (427 ng/L), the diuretic hydrochlorothiazide (445 ng/L) and the psychiatric drug carbamazepine (99 ng/L). The antibiotic ciprofloxacin exhibited the highest concentration in the biofilm (179 ng/g d.w.) and in the macrophyte L. gibba (112 ng/g d.w.) Several compounds were detected in the water but not in the biota (e.g., codeine and bezafibrate), and others (e.g., azithromycin and citalopram) were found in the biota but not in the surface water. Significant bioaccumulation factors (>1000 L/kg d.w.) were obtained for venlafaxine and ciprofloxacin in biofilm. Our results show that PhACs may accumulate in several biological compartments. Within an environmental compartment, similar PhACs profile and concentrations were found in different sites receiving urban pollution. Among different compartments, biofilms may be the most suitable biota matrix to monitor the immediate reception of PhACs in the biota. Our results indicate that the presence of PhACs in urban rivers and their accumulation in the biota could be incorporated as symptoms of the urban stream syndrome.

Pharmaceuticals and environmental risk assessment in municipal wastewater treatment plants and rivers from Peru

This is the first study dealing with removal of the pharmaceutical substances in municipal wastewater treatment plants (MWWTPs) from Peru and the impact of these compounds in surface waters receiving treated wastewater. To this aim, samples from MWWTP of Lima (Peruvian Coast), MWWTP of Cusco, Puno and Juliaca (Peruvian Highlands), as well surface water (confluence of Torococha and Coata rivers in Juliaca) were analyzed. A total of 38 target pharmaceuticals were included in this study and were determined by Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS). Around 60% and 75% of the target pharmaceuticals could be quantified in surface water and MWWTPs, respectively. Acetaminophen was the drug found at the highest concentration, and it was present in all the treated wastewater samples reaching average values above 100 μg/L in the department of Puno. The gabapentin anti-epileptic drug (up to 11.85 μg/L in MWWTP Lima) and the antibiotics clarithromycin, trimethoprim, ciprofloxacin, sulfamethoxazole and azithromycin (1.86 to 4.47 μg/L in MWWTP Lima) were also found at moderate concentrations in the treated wastewater. In surface water, the highest concentration corresponded also to acetaminophen (28.70 μg/L) followed by sulfamethoxazole (4.36 μg/L). As regards the pharmaceuticals removal, data of this work showed that the MWWTP Cusco (aerobic biologic process by synthetic trickling filters as secondary treatment) was more efficient than the MWWTP Lima (a preliminary treatment that combines grilles, sand trap, degreaser-aerated and sieved of 1.0 mm). However, many pharmaceuticals (around 50% of the compounds investigated) presented concentrations in treated wastewater similar or even higher than in influent wastewater. The environmental ecological risk of pharmaceuticals was assessed based on calculated Risk Quotient (RQ) in the treated wastewater and surface water from the concentration data found in the samples. According to our data, three antibiotics (clarithromycin, ciprofloxacin, clindamycin) and the analgesic acetaminophen posed high environmental risk (RQ ≥ 1) on the aquatic environment. In the river, all antibiotics (except norfloxacin) as well as the analgesic-anti-inflammatory compounds acetaminophen, diclofenac posed a high environmental risk (RQ ≥ 1). Based on data reported in this work for the first time in water samples from Peru, it can be deduced that the treatment processes applied in important cities from Peru are not enough efficient to remove pharmaceuticals in wastewater. As a consequence, severe environmental risks associated to the presence of pharmaceuticals in treated wastewater and surface water are expected; so complementary treatment processes should be implemented in the MWWTPs for a more efficient elimination of these compounds.

MO492SELF-REPORTED MEDICATION USE AND URINARY DRUG METABOLITES IN THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY: A PHARMACOMETABOLOMIC APPROACH

Abstract Background and Aims Chronic kidney disease (CKD) patients are prone to prescription of multiple medications. Medication adherence is a well-recognized problem in the management of patients with chronic diseases requiring polypharmacy. This study aimed to evaluate the connection between self-reported medication use and urine drug metabolite levels in a large cohort of CKD patients, the GCKD study, as a basis for future pharmacometabolomics studies. Method Self-reported medication use of 160 substances and 41 medication groups was ascertained at study baseline and coded according to the Anatomical Therapeutic Chemical classification system. A non-targeted mass spectrometry-based approach (Metabolon HD4™) was used for concomitant metabolite quantification in urine. Specificity, sensitivity and accuracy of medication use and the corresponding urine metabolite measurements were calculated. Multivariable regression models (adjusted to age, sex, eGFR, log(UACR), systolic blood pressure, LDL, log(triglycerides), log(HBA1c) were used to establish associations in prescription patterns. Results Among 4,885 participants, 78 drug metabolites were detected in urine (frequency range: 0.4-58%) and assigned into 110 medication – drug metabolite pairs (MMPs) based on reported individual substances and medication groups. For all 68 MMPs of individual substances, accuracy of medication use and the corresponding drug metabolite measurement was excellent (median 97.0%, range 43%-100%), as was measurement-based specificity (median 99.3%, range 73.3%-100%; Fig. 1). Median measurement-based sensitivity was 72.1% (range 1.1%-100%, Fig. 1). Sensitivity and specificity were especially high for angiotensin-II receptor blockers (92%-96%; 99-100%), calcium channel blockers (85-100%; 91-100%), and metoprolol (90%; 98% respectively) commonly prescribed and important medications for blood pressure control and cardiovascular risk reduction in CKD patients. MMPs showing sensitivity <80% included several substances found in over-the-counter (OTC) analgesic medications, suggesting that their use is not always reported. While self-reported use of the OTC analgesics acetaminophen and ibuprofen was <3% each, their corresponding drug metabolites indicated higher usage (acetaminophen: 10-26%; ibuprofen: 10-18%, depending on the number of evaluated drug metabolites). Typical examples of medication co-prescriptions (e.g., trimethoprim and sulfamethoxazole) were detected as the combined presence of their drug metabolites in urine. This result validates the abstraction of single substances from combination medications and this urine-based metabolomic approach. Conclusion This study provides a comprehensive screen of the associations between urine drug metabolite levels and self-reported medication use. It supports the usefulness of pharmacometabolomics to assess medication use, frequency of OTC analgesics use, and prescription patterns in persons with CKD.

G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity

Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.

Tumescent local anesthesia versus general anesthesia for subcutaneous implantable cardioverter-defibrillator implantation

Subcutaneous implantable cardioverter-defibrillator (S-ICD) is an effective alternative to transvenous implantable cardioverter-defibrillator. General anesthesia (GA) is considered the standard sedation approach because of the pain caused by the manipulation of subcutaneous tissue with S-ICD implantation. However, GA carries several limitations, including additional risk of adverse events, prolonged in-room times, and increased costs. The purpose of this study was to define the effectiveness and safety of tumescent local anesthesia (TLA) in comparison to GA in patients undergoing S-ICD implantation. We performed a prospective, nonrandomized, controlled, multicenter study of patients referred for S-ICD implantation between 2019 and 2020. Patients were allocated to either TLA or GA on the basis of patient's preferences and/or anesthesia service availability. TLA was prepared using lidocaine, epinephrine, sodium bicarbonate, and sodium chloride. All patients provided written informed consent, and the institutional review board at each site provided approval for the study. Sixty patients underwent successful S-ICD implantation from July 2019 to November 2020. Thirty patients (50%) received TLA, and the rest GA. There were no differences between groups with regard to baseline characteristics. In-room and procedural times were significantly shorter with TLA (107.6 minutes vs 186 minutes; P < .0001 and 53.2 minutes vs 153.7 minutes; P < .0001, respectively). Pain was reported less frequently by patients who received TLA. The use of opioids was significantly reduced in patients who received TLA (23% vs 62%; P = .002). TLA is an effective and safe alternative to GA in S-ICD implantation. The use of TLA is associated with shorter in-room and procedural times, less postprocedural pain, and reduced usage of opioids and acetaminophen for analgesia.

Efficient removal of pharmaceuticals from water using graphene nanoplatelets as adsorbent.

Recently, pharmaceutical pollutants in water have emerged as a global concern as they give threat to human health and the environment. In this study, graphene nanoplatelets (GNPs) were used to efficiently remove antibiotics sulfamethoxazole (SMX) and analgesic acetaminophen (ACM) as pharmaceutical pollutants from water by an adsorption process. GNPs; C750, C300, M15 and M5 were characterized by high-resolution transmission electron microscopy, Raman spectroscopy, X-ray diffraction and Brunauer–Emmett–Teller. The effects of several parameters viz. solution pH, adsorbent amount, initial concentration and contact time were studied. The parameters were optimized by a batch adsorption process and the maximum removal efficiency for both pharmaceuticals was 99%. The adsorption kinetics and isotherms models were employed, and the experimental data were best analysed with pseudo-second kinetic and Langmuir isotherm with maximum adsorption capacity (Qm) of 210.08 mg g−1 for SMX and 56.21 mg g−1 for ACM. A regeneration study was applied using different eluents; 5% ethanol-deionized water 0.005 M NaOH and HCl. GNP C300 was able to remove most of both pollutants from environmental water samples. Molecular docking was used to simulate the adsorption mechanism of GNP C300 towards SMX and ACM with a free binding energy of −7.54 kcal mol−1 and −5.29 kcal mol−1, respectively, which revealed adsorption occurred spontaneously.

Caudal versus intravenous ketamine for supplementation of analgesia in children undergoing hypospadias repair: a randomized controlled trial

Background Different additives have been reported to prolong the duration of caudal anesthesia in pediatrics. Although these drugs successfully increased the duration of the block, ketamine has been found to effectively increase the duration of caudal block in pediatrics. Aim This study aimed to assess the clinical effectiveness of ketamine after caudal or intravenous administration in pediatric patients who underwent hypospadias repair to distinguish between local and systemic analgesia. Patients and methods After induction of general anesthesia, 48 patients, aged 1–6 years, assigned to undergo hypospadias repair, received a caudal injection of bupivacaine and were randomly blinded into two groups: K1 group received 1 mg/kg S-ketamine as the caudal group, and K2 group received 1 mg/kg S-ketamine as the intravenous group. Postsurgical measurements included the effectiveness of postsurgical analgesia, which was assessed by using observational pain scale, duration of analgesia, sedation score, and hemodynamic and complications. Results The caudal block was successful in all the patients included in the study. None of the patients in either groups required intraoperative rescue analgesia. All patients remained vitally stable during the procedure, and intraoperative hemodynamic parameters were comparable in the two groups. The time to the administration of first analgesia was statistically longer in K1 group (11.5±4.6 h) than in the K2 group (8.7±3.1 h). Time to spontaneous leg movement and time to first micturition were statistically nonsignificant between both groups. The number of patients requested for additional analgesic drugs (acetaminophen and ibuprofen) was statistically significant, being higher in the K2 group than the K1 group. Conclusion This study demonstrates that ketamine if added to caudal epidural in a dose of 1 mg/kg provided prolonged postoperative analgesia with improved quality, had longer duration of analgesia, decreased the supplemental acetaminophen analgesia during the first 24 h postoperatively, had stable hemodynamic changes, and had comparable adverse effects and complications in comparison with systemic ketamine in a dose of 1 mg/kg.

Human pharmaceuticals in marine mussels: Evidence of sneaky environmental hazard along Italian coasts

Despite the increasing interest for pharmaceuticals in the marine environment, their accumulation in wild organisms and consequent environmental hazards are still poorly known. The Mediterranean Sea is highly challenged by the density of coastal populations, large consumption of pharmaceuticals and their often limited removal by Wastewater Treatment Plants (WWTPs). In this respect, the present study aims to provide the first large-scale survey on the distribution of such contaminants of emerging concern in native mussels, Mytilus galloprovincialis from Italian coasts. Organisms were collected from 14 sites representative of relatively unpolluted marine waters along the Adriatic and Tyrrhenian Sea and analysed for 9 common pharmaceuticals including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs: Diclofenac DIC, Ibuprofen IBU, Ketoprofen KET and Nimesulide NIM), the analgesic Acetaminophen AMP, the antiepileptic Carbamazepine CBZ, the antihypertensive Valsartan VAL, the anxiolytic Lormetazepam LOR and the antidepressant Paroxetine PAR. Results indicated the widespread occurrence of the majority of pharmaceuticals in mussel tissues: CBZ was measured in >90% of analysed samples, followed by VAL (>50%), PAR (>40%), and DIC (>30%), while only AMP and KET were never detected. Heterogeneous tissue concentrations ranged from a few units up to hundreds of ng/g (d.w.), while seasonal and interannual variability, investigated over 4 years, did not highlight any clear temporal trend. Limited differences obtained between the Adriatic and Tyrrhenian Sea, as well as coastal versus off-shore sampling sites, suggest that analysed levels of pharmaceuticals in mussels tissues should be considered as baseline concentrations for organisms collected in unpolluted areas of the Mediterranean. This study provided the first unambiguous evidence of the widespread occurrence of pharmaceuticals in marine mussels from Italian coasts, giving novel insights on the potential ecotoxicological hazard from such compounds in marine species.

The association between analgesic drug use in pregnancy and neurodevelopmental disorders: protocol for an umbrella review

BackgroundMaternal prenatal health has been shown to be an important influence on children’s developmental outcomes, which has led to an increased emphasis on providing more information to support clinical decisions in pregnancy. Several systematic reviews suggest that analgesic drug use during pregnancy may have neurodisruptive properties. However, no firm conclusions have yet been drawn on the associations between prenatal analgesic drug use and children’s long-term development of neurodevelopmental disorders such as autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD). Therefore, an umbrella review is proposed for the purpose of examining the associations between maternal analgesic drug use during pregnancy and diagnoses of neurodevelopmental disorders.MethodsIncluded systematic reviews will consist of studies examining the effect of maternal prenatal analgesic drug use, specifically ibuprofen, acetaminophen, aspirin, naproxen, diclofenac, and ketoprofen, on children’s neurodevelopmental disorder status. Examined drugs were restricted to those readily accessible and frequently used by pregnant women, and with characteristics that allow them to cross the placenta and directly affect fetal development. Outcomes will be restricted to formal clinical diagnoses of ASD and/or ADHD. Two reviewers will independently identify eligible reviews from six databases (e.g., PubMed, EMBASE, PsychINFO) from inception dates of databases to the date of data extraction, and conduct manual searches of reference lists, consultation with field experts, and scan of pre-print archives. Extracted data will also include short qualitative summaries by both reviewers. As part of quality assessment, a standardized measurement tool to assess systematic reviews (AMSTAR 2) will be used. A narrative synthesis is proposed to integrate findings from different, potentially methodologically heterogeneous, studies.DiscussionThis umbrella review of associations between maternal prenatal use of analgesic drugs and children’s neurodevelopmental disorders could allow for firmer conclusions to be drawn through the synthesis of all relevant published research. The synthesis of findings using high-quality evidence could provide more accurate healthcare information on the long-term effects of analgesic drugs on neurodevelopment, to better guide future clinical decisions during pregnancy. This review will also allow gaps and methodological differences in the literature to be identified, informing recommendations for future research.Systematic review registrationPROSPERO CRD42020179216.

Mining and visualizing high-order directional drug interaction effects using the FAERS database

BackgroundAdverse drug events (ADEs) often occur as a result of drug-drug interactions (DDIs). The use of data mining for detecting effects of drug combinations on ADE has attracted growing attention and interest, however, most studies focused on analyzing pairwise DDIs. Recent efforts have been made to explore the directional relationships among high-dimensional drug combinations and have shown effectiveness on prediction of ADE risk. However, the existing approaches become inefficient from both computational and illustrative perspectives when considering more than three drugs.MethodsWe proposed an efficient approach to estimate the directional effects of high-order DDIs through frequent itemset mining, and further developed a novel visualization method to organize and present the high-order directional DDI effects involving more than three drugs in an interactive, concise and comprehensive manner. We demonstrated its performance by mining the directional DDIs associated with myopathy using a publicly available FAERS dataset.ResultsDirectional effects of DDIs involving up to seven drugs were reported. Our analysis confirmed previously reported myopathy associated DDIs including interactions between fusidic acid with simvastatin and atorvastatin. Furthermore, we uncovered a number of novel DDIs leading to increased risk for myopathy, such as the co-administration of zoledronate with different types of drugs including antibiotics (ciprofloxacin, levofloxacin) and analgesics (acetaminophen, fentanyl, gabapentin, oxycodone). Finally, we visualized directional DDI findings via the proposed tool, which allows one to interactively select any drug combination as the baseline and zoom in/out to obtain both detailed and overall picture of interested drugs.ConclusionsWe developed a more efficient data mining strategy to identify high-order directional DDIs, and designed a scalable tool to visualize high-order DDI findings. The proposed method and tool have the potential to contribute to the drug interaction research and ultimately impact patient health care.Availability and implementationhttp://lishenlab.com/d3i/explorer.html

Acetaminophen-induced apoptosis: facts versus fiction

Hepatotoxicity and acute liver failure caused by an acetaminophen overdose is a serious clinical problem in western countries. Understanding the mode of cell death and the signaling pathways involved is critical for developing new therapeutic approaches. Recent trends to claim that apoptosis is a relevant mode of cell death in acetaminophen hepatotoxicity are not justified by sound scientific data and will not lead to effective new drug development.

Universal Anesthesia Machine: Clinical Application in an Austere, Resource-Limited Environment.

In austere environments, the safe administration of anesthesia becomes challenging because of unreliable electrical sources, limited amounts of compressed gas, and insufficient machine maintenance capabilities. Such austere environments exist in battlefield medicine, in low- and middle-income countries (LMICs), and in areas struck by natural disasters. Whether in military operations or civilian settings, the Universal Anesthesia Machine (UAM) (Gradian Health Systems, New York, New York) is a draw-over device capable of providing safe and effective general anesthesia when external oxygen supplies or reliable electrical sources are limited. This brief report discusses a proof-of-concept observational study demonstrating the clinical utility of the UAM in a resource-limited area. This observational study of 20 patients in Haiti who underwent general anesthesia using the UAM highlights the device's capability to deliver anesthesia intraoperatively in a resource-limited LMIC clinical setting. Preoxygenation was achieved with the UAM's draw-over oxygen supply. Patients received acetaminophen for analgesia, dexmedetomidine for preinduction anesthesia, and succinylcholine for paralysis. After induction, the UAM provided a mixture of oxygen and isoflurane for maintenance of anesthesia. Manual ventilation was performed using draw-over bellows until spontaneous ventilation recurred, when clinically appropriate, artificial airways were removed. Intraoperative medication was administered at the anesthesiologist's discretion. The institutional review board at the U.S. anesthesiologists' affiliated institution and the Haitian hospital approved this study; patients were consented in their native language. Two anesthesiologists used the UAM to deliver general anesthesia to 20 patients in a Haitian hospital without access to an external oxygen supply, reliable power grid, or opioids. The patients' average age was ~40years, and 90% of them were male. Most of the cases were herniorrhaphy (50%) and hydrocelectomy (25%) surgeries. The median American Society of Anesthesiologists (ASA) score was 2; 45% of the patients had an ASA score of 1, and none had an ASA score >3. Of the 20 cases, 55% of patients received an endotracheal tube, and 40% received a laryngeal mask airway; for one patient, only a masked airway was used. Every patient was discharged on the day of the surgery. No complications occurred in the perioperative or 1-month follow-up period. The UAM can be used where a lack of resources and training exist because of its simple design, built-in oxygen concentrator, and capacity to revert from continuous-flow to draw-over anesthesia in the event of a power failure or if external oxygen supplies are unavailable. We believe the UAM addresses some of the shortcomings of modern anesthesia machines and has the potential to improve the delivery of safe general anesthesia in combat and austere scenarios. Further studies could consider different types of surgeries than those reported here and involve more complex patients. Studies involving alternative anesthetic agents and non-anesthesiologist personnel are also needed. Overall, this brief report detailing the use of the UAM following a natural disaster in a LMIC is proof of concept that the machine can provide reliable anesthesia for surgical procedures in austere and resource-limited environments, including disaster areas and modern combat zones.