Search

Preservation of hepatic phenotype and functions in vitro has always been a great challenge for the reconstruction of liver tissue engineering and in pharmaceutical research studies. Human induced hepatocytes (hiHeps) generated from fibroblasts can be reproducible with almost normal levels of liver specific functions, which are considered as a new source of hepatocytes for biomedical applications. Moreover, paper has served as an attractive biocompatible material for cell-based applications. In this study, we established a simple paper-based scaffold array for creating a 3D liver co-culture model that enabled the assessment of drug induced hepatotoxicity. The hiHeps co-cultured with HUVECs exhibited a 3D like morphology and maintained the liver specific functions of producing albumin and urea for up to 2 months. In addition, the hiHeps in this co-cultured model maintained a higher expression of cytochrome P450 genes as compared with a monolayer culture on a plate and a single culture on paper of hiHeps, revealing a marked enhancement of hepatic functions in the 3D liver co-culture model. Moreover, the 3D liver co-culture model was exposed to acetaminophen (APAP) and pioglitazone, exhibiting near physiological hepatotoxic responses compared to those of the monolayer cultures. Taken together, the low-cost and bioactive paper scaffold could offer great opportunities as 3D in vitro platforms for tissue engineering applications and high-throughput drug testing. [ABSTRACT FROM AUTHOR]

Tardigrades in their natural environment are exposed to various environmental toxicants, including non-steroidal anti-inflammatory drugs (NSAIDs) or antipyretics such as paracetamol. This drug can enter the animal's body through the body wall or the digestive system with food and can affect the biology of organisms. In this paper, we report for the first time the effects of paracetamol on tardigrade storage cells. We analyzed the effects of short-term (7 days) and long-term (28 days) exposure of Hypsibius exemplaris storage cells to three paracetamol concentrations (0.2 µgxL−1, 230 µgxL−1, 1 mgxL−1). Our results showed that increasing paracetamol concentration and incubation time increases the number of damaged mitochondria in storage cells, and autophagy is activated and intensified. Moreover, the relocation of some organelles and cell deformation may indicate cytoskeleton damage. [ABSTRACT FROM AUTHOR]

Medication use is often underreported in paper-based questionnaires or interviews.Web-based questionnaires may improve recall ofmedication use, but data on their validity are currently lacking. Participants in the Pregnancy and Infant Development (PRIDE) Study (2014-2016; n = 557) and the Pregnancy Drug Registry (pREGnant) (2015-2016; n = 169) completed a 6-week paper-based medication diary during gestational weeks 19-24 or 26-31. In week 34, they completed a Web-based questionnaire with questions on medication names, time period and frequency of use, and quantity taken. To assess the degree of underreporting, we calculated the questionnaire's sensitivity using the medication diary as the reference standard. Sensitivity was high formany medication groups, including antiepilepticmedication (sensitivity (Sn) = 0.96, 95% confidence interval (CI): 0.89, 1.00), antacids (Sn = 0.89, 95% CI: 0.86, 0.93), and iron preparations (Sn = 0.81, 95% CI: 0.64, 0.98). However, medications for short-term use were underreported more frequently, with sensitivities of 0.54 (95% CI: 0.35, 0.72) for antihistamines, 0.63 (95% CI: 0.57, 0.69) for analgesic and antipyretic agents, and 0.57 (95% CI: 0.51, 0.64) for acetaminophen. Shortening the period of time between exposure and questionnaire administration increased sensitivity substantially. In conclusion, underreporting in Web-based questionnaires is limited for many medication groups. In prospective studies, underreporting of medications for short-term usemay be reduced by decreasing the interval between consecutive questionnaires. medication use; pregnancy; Pregnancy Drug Registry (pREGnant); Pregnancy and Infant Development (PRIDE) [ABSTRACT FROM AUTHOR]

Study Question: Are boys who are born to mothers who use analgesics during pregnancy at increased risk of cryptorchidism compared to those born to mothers who do not take analgesia?Summary Answer: In this systematic review and meta-analysis of 10 published studies, we observed only weak evidence of an association between analgesia use during pregnancy and risk of cryptorchidism in the son.What Is Known Already: Concentrations of analgesia relevant to human exposure have been implicated as causing endocrine disturbances in the developing foetal testis. However, when viewed collectively there appears to be conflicting evidence regarding an association between maternal use of analgesics and development of cryptorchidism.Study Design, Size, Duration: A systematic review and meta-analysis of studies on analgesia use during pregnancy and risk of cryptorchidism was performed. The search terms used were (analges* OR paracetamol OR acetaminophen) AND (cryptorchidism OR cryptorchism OR undescended test* OR non-descended test* OR non descended test*) for the databases Ovid Medline, Embase, Scopus and Web of Science. The search included all published articles up until 23 May 2016 and no limits were set in terms of language.Participants/materials, Setting, Methods: Abstracts were screened by one reviewer to remove irrelevant studies, with a 10% random sample of these verified by a second reviewer. The full text of all remaining papers was assessed by two reviewers. Abstracts included in the final analysis were studies which reported associations between the exposure (analgesia) and the outcome (cryptorchidism). Studies were only included if data were provided from which summary associations (odds ratios (ORs) or relative risks) and their 95% CIs could be calculated, or if summary associations were provided by the authors themselves. For each included study, two reviewers independently extracted study meta-data in line with PRISMA recommendations. We assessed study quality and potential for bias using the criteria outlined in the Newcastle-Ottawa Quality Assessment Scale, but did not determine a quality score. Two reviewers independently assessed study quality against these criteria.Main Results and the Role Of Chance: After screening 350 manuscripts, 10 were included in our review (5 case-control studies, 5 cohort studies). We observed weak evidence of an association between ever use of analgesia and risk of cryptorchidism (pooled crude OR: 1.11, 95% CI: 1.00-1.23), with case-control studies revealing a marginally stronger association (1.23, 95% CI: 0.85-1.78) than cohort studies (1.09, 95% CI: 0.97-1.22). We observed weak evidence of a dose-response relationship between increasing weeks of analgesia exposure and risk of cryptorchidism, as well as weak evidence of an effect of timing on analgesia exposure and risk of cryptorchidism. Assessment of study quality via the Newcastle-Ottawa criteria revealed little (if any) evidence of substantial bias that may have meaningfully affected a given study's results.Limitations, Reasons For Caution: While confounding does not appear to be important, misclassification of the exposure is possibly an important source of measurement error in this context. The systematic review is open to reporting bias. Owing to scant data, no meta-analyses for two key questions (relating to dose-response and timing of exposure) could be performed. Medications were grouped based on their common effect and this offers little insight into the relation between specific types of analgesia and cryptorchidism. Finally, there are limitations in assuming that analgesia use reported by mothers is synonymous with actual intrauterine exposure.Wider Implications Of the Findings: The ubiquity of analgesia use during pregnancy makes this exposure particularly important from a population health perspective. About 9 of the 10 studies were conducted in Europe or USA, limiting generalizability of our observations. While the observations from our systematic review and meta-analysis suggest that analgesia use during pregnancy is not strongly associated with cryptorchidism development in the son, they also highlight the need for further detailed assessments of this relationship.Study Funding/competing Interest(s): This study was funded by the Health Research Council of New Zealand (reference #: 14/052). The authors have no conflict of interest to declare.Registration Number: CRD42016041414. [ABSTRACT FROM AUTHOR]

The article by Keaveney et al. entitled 'Effects of acetaminophen on risk taking' was published in July of 2020 and concluded that using acetaminophen increased risk-taking behaviors, potentially by reducing perceived risk. We believe that there is not enough data to support the generalization of this association and feel that the conclusions were presented without acknowledgement of the limitations of this study. Media articles often further dramatized these findings, presenting the potential correlation between acetaminophen and risk taking as fact. It is unfair to readers to sensationalize the associations seen in controlled experiments in an attempt to generalize the study's findings. As scientists, we need to assure that the discussions and conclusions presented in publications appropriately highlight the limitations of studies. We must also work to assure that the public does not sensationalize preliminary and limited research results. [ABSTRACT FROM AUTHOR]

Objectives The aim of this research paper was to investigate the hepatoprotective and antioxidant effects of gallic acid in paracetamol-induced liver damage in mice. Methods In the present study, the hepatoprotective and antioxidant effects of gallic acid were evaluated against paracetamol-induced hepatotoxicity in mice and compared with the silymarin, a standard hepatoprotective drug. The mice received a single dose of paracetamol (900 mg/kg body weight i.p.). Gallic acid (100 mg/kg body weight i.p.) and silymarin (25 mg/kg body weight i.p.) were administered 30 min after the injection of paracetamol. After 4 h, liver marker enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase) and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while the lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione- S-transferase and glutathione) were determined in liver homogenate of the control and experimental mice. Key findings Increased activities of liver marker enzymes and elevated TNF-α and lipid peroxidation levels were observed in mice exposed to paracetamol ( P < 0.05), whereas the antioxidant status was found to be depleted ( P < 0.05) when compared with the control group. However gallic acid treatment (100 mg/kg body weight i.p.) significantly reverses ( P < 0.05) the above changes by its antioxidant action compared to the control group as observed in the paracetamol-challenged mice. Conclusions The results clearly demonstrate that gallic acid possesses promising hepatoprotective effects. [ABSTRACT FROM AUTHOR]

Background About 500 drug poisoning deaths involving paracetamol (acetaminophen) occur every year in England and Wales. To reduce the number of deaths, regulations were introduced in 1998 to restrict the sale of paracetamol. In this paper, we evaluate the impact of these regulations. [ABSTRACT FROM PUBLISHER]

Background Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes pre-plasma B cells. It is used in paediatric rheumatology for conditions including juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), vasculitides and refractory juvenile idiopathic arthritis (JIA). We aim to describe the cohort of patients treated with rituximab in the Scottish Paediatric and Adolescent Rheumatology Network (SPARN) in a 5-year period, and assess the need for a network guideline. Methods A review of paper and electronic case records. Patients seen within the SPARN network who received Rituximab between 2014 and 2018 were included. Results Vasculitis Rituximab was given to 16 patients in 5 different SPARN centres between 2014 and 2018. Male: Female ratio was 1:4.3. Mean age at first dose of rituximab was 12.75 years. Mean disease duration pre rituximab was 1 year. 8 (50%) patients had jSLE, 7 multisystem and 1 isolated lupus nephritis. 3 had ANCA-positive vasculitis and 5 had other conditions. (1 had RF+ve JIA; 1 severe panuveitis; 1 had an unspecified autoinflammatory condition; 1 had COPA syndrome with severe interstitial lung disease and 1 had autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Documentation of pre-rituximab checks was poor. Baseline bloods were done in all 16 patients. 11 patients had lymphocyte subsets and 13 immunoglobulins documented. Disease-specific antibodies were measured in all patients in whom applicable (11). 11 had a chest x-ray prior to rituximab. In 9 cases a pre-rituximab pregnancy test was indicated: none were documented. In only 3 patients was a pre-rituximab history of recent infections documented. In 8 patients a discussion regarding treatment risks and benefits was documented. Post-infusion lymphocyte subset monitoring was variable but documented in 15. 1 patient was never B cell deplete. 9 never fully reconstituted. RTX dose information was available for 14. All received doses of 750mg/m2 with 6 having the dose capped at 1g. Dose frequency information was available for all. The majority (9) received 2 doses. Of the rest, 1 patient received a single dose. 3 received 3 doses, 2 had 4 and 1 had 5. All patients in whom information was available, received pre-medication with paracetamol, chlorphenamine and methylprednisolone (n = 14). 4 patients had side effects noted (rash/itch in 1, anaphylaxis in 1, facial flushing in 1 and post-infusion infection in 1). Clinical response was clearly documented in 8 patients, 7 of whom showed clinical improvement (2 had systemic jSLE, 2 had ANCA +ve vasculitis, 1 had isolated lupus nephritis, 1 had COPA syndrome and 1 had RF+ JIA). Conclusion Rituximab is used for a range of conditions and in a number of centres within SPARN. This review highlights variation in and poor documentation of pre-rituximab discussions and investigations, prescribing, monitoring and response. A SPARN rituximab protocol is being developed to address this. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: The management of patients with acetaminophen (APAP) toxicity is largely informed by the blood concentration. We sought to assess the analytical characteristics of past and current commercial APAP assays in the United States. Methods: We systematically reviewed the analytical characteristics of APAP assays cleared by the Food and Drug Administration's (FDA) 510(k) premarket notification process by searching the Clinical Laboratory Improvement Amendments (CLIA) database. We collected the following data where available: test principle, precision near 10 mg/L, precision near 150 mg/L, limits of detection, and limits of quantitation. Results: For all assays, absolute analytical precision decreased as analyte concentration increased. Near [APAP] = 10 mg/L, the most precise assays had a standard deviation (SD) of 0.2 mg/L or coefficient of variation (CV) of 1% and the least precise assays had a SD of 1.8 mg/L or a CV of 10%. Near [APAP] = 150 mg/L, the most precise assay had a SD of 1.4 mg/L or CV of 0.9% and the least precise assays had a SD of 7.4 mg/L or a CV of 4.9%. Conclusions: Commercially available APAP assays had good analytical precision with improvement over time. The failure of some manufacturers to validate precision near treatment thresholds is concerning. Newer APAP assays can measure a wider range of [APAP], which likely improves the risk stratification of overdose patients but also carries a risk of overdiagnosis when minuscule quantities are detected. [ABSTRACT FROM AUTHOR]

Acetaminophen (N -acetyl- p -aminophenol paracetamol (APAP)) toxicity is one of the commonly encountered poisonings by emergency physicians. Methemoglobinemia is an uncommon association and rarely seen in APAP poisoning. The study involves the retrospective analysis of all the published reports on APAP-induced methemoglobinemia from 1968 to 2019.   In total, there were 14 cases with nine females and six males. The median age of the study cohort was 59 years. The most common presenting feature was altered mentation (nine patients) followed by cyanosis (three patients). The intent of consumption was therapeutic (seven cases) vs. suicidal (five cases) attempt. In most cases, the dose of APAP consumption was not known. Aspirin, sulfasalazine, benzocaine spray, nitrate preservative, contaminated water, detergents, and so on where the other agents consumed by the patients in addition to APAP before developing methemoglobinemia. The median MethHb level of the study cohort was 15.85%. Patients were treated with NAC, hemodialysis, methylene blue and ascorbic acid and continuous renal replacement therapy in various combinations. Full recovery was seen in nine patients while four patients died.   APAP toxicity is a well-known and a common entity with multiple sequelae that presents with a variable spectrum of mild to fulminant multiorgan failure. Awareness of non-classical presentations like methemoglobinemia is essential to ensure timely intervention. [ABSTRACT FROM AUTHOR]

More predictive in vitro liver models are a critical requirement for preclinical screening of compounds demonstrating hepatotoxic liability. 3D liver spheroids have been shown to have an enhanced functional lifespan compared to 2D monocultures; however a detailed characterisation of spatiotemporal function and structure of spheroids still needs further attention before widespread use in industry. We have developed and characterized the structure and function of a 3D liver spheroid model formed from C3A hepatoma cells. Spheroids were viable and maintained a compact in vivo-like structure with zonation features for up to 32 days. MRP2 and Pgp transporters had polarised expression on the canalicular membrane of cells in the spheroids and were able to functionally transport CMFDA substrate into these canalicular structures. Spheroids expressed CYP2E1 and were able to synthesise and secrete albumin and urea to a higher degree than monolayer C3A cultures. Penetration of doxorubicin throughout the spheroid core was demonstrated. Spheroids showed increased susceptibility to hepatotoxins when compared to 2D cultures, with acetaminophen having an IC50 of 7.2 mM in spheroids compared to 33.8 mM in monolayer culture. To conclude, we developed an alternative method for creating C3A liver spheroids and demonstrated cellular polarisation and zonation, as well as superior liver-specific functionality and more sensitive toxicological response compared to standard 2D liver models, confirming a more in vivo-like liver model. [ABSTRACT FROM AUTHOR]

Objectives Acetaminophen (APAP) overdose has been the primary cause of drug-induced liver injury (DILI) in western countries. Monoammonium glycyrrhizinate (MG) is a primary active ingredient from glycyrrhiza. Cysteine hydrochloride (CH) is a component of glutathione (GSH). The study aimed to explore the therapeutical effect of MG-CH against DILI incurred by intragastric APAP. Methods Mice were randomized into eight groups: control, APAP, three groups accepted APAP and the combination of MG and CH (15, 30, 60 mg/kg), two groups accepted APAP and MG (40 mg/kg) or CH (20 mg/kg), moreover, one group received MG-CH (60 mg/kg) without APAP. After pretreatment with MG-CH or MG and CH alone for 3 days, mice were administered APAP by oral gavage. The serum and tissue were collected to detect the activities of liver enzymes and evaluate the change of histomorphology and explore the possible mechanism of MG-CH in protecting against DILI. Key findings MG-CH pretreatment remarkably alleviated hepatic injury and decreased the activities of ALT, AST, ALP and LDH. The hepatic ROS and MDA contents were decreased, and the level of GSH and GSH-PX activities was increased in the serum. Furthermore, MG-CH improved the expression of Nrf2, HO-1, GCLM and NQO1 to increase antioxidant ability and induce detoxification. The expression of IL-10 suppressing excessive inflammatory responses was enhanced. Conclusion The study demonstrated that MG-CH had protective effects against DILI induced by APAP and the potential mechanisms were based on inhibiting oxidative stress and activating the Keap1/Nrf2/ARE pathway. [ABSTRACT FROM AUTHOR]

Background: Inflammation is a central pathway leading to frailty but whether commonly used nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent frailty is unknown.Methods: Prospective cohort study of male physicians ≥60 who participated in the Physicians' Health Study. Annual questionnaires collected data on NSAID use, lifestyle, and morbidity. Average annual NSAID use was categorized as 0 days/year, 1-12 days/year, 13-60 days/year, and >60 days/year. Frailty was assessed using a validated 33-item frailty index. Propensity score inverse probability of treatment weighting was used to address confounding by indication and logistic regression models estimated odds ratios (ORs) of prevalent frailty according to nonaspirin NSAID use.Results: A total of 12 101 male physicians were included (mean age 70 ± 7 years, mean follow-up 11 years). Reported NSAID use was 0 days/year for 2 234, 1-12 days/year for 5 812, 13-60 days/year for 2 833, and >60 days/year for 1 222 participants. A total of 2 413 participants (20%) were frail. Higher self-reported NSAID use was associated with greater alcohol use, smoking, arthritis, hypertension, and heart disease, while less NSAID use was associated with coumadin use and prior bleeding. After propensity score adjustment, all characteristics were balanced. ORs (95% confidence intervals) of prevalent frailty were 0.90 (0.80-1.02), 1.02 (0.89-1.17), and 1.26 (1.07-1.49) for average NSAID use of 1-12 days/year, 13-60 days/year, and >60 days/year, compared to 0 days/year (p-trend < .001).Conclusions: Long-term use of NSAIDs at high frequency is associated with increased risk of frailty among older men. Additional study is needed to understand the role of anti-inflammatory medication in older adults and its implication for overall health. [ABSTRACT FROM AUTHOR]

Objectives: Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation. Methods: Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates. Key findings: Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6. Conclusions: Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures. [ABSTRACT FROM AUTHOR]

Objectives To describe and map what is known about unconventional uses of paracetamol through a scoping review of published literature by adopting adopted a PRISMA systematic approach methodology. Key findings Four themes for unconventional uses of paracetamol emerged: (a) use of paracetamol in sleep (a-1) positive effect of paracetamol on sleep (n = 9) or (a-2) neutral or negative effect of paracetamol on sleep (n = 9); (b) use of paracetamol in sport (n = 13); (c) mixing paracetamol with drinks, waterpipe and illicit drugs (n = 5); and (d) miscellaneous uses (n = 4). Forty records were reviewed and charted. Available literature supports concern around the potential of harmful or non-medical use of paracetamol, especially among patients with a history of substance use, parents of young children or athletes. Summary Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It is considered remarkably safe if used within instructions. However, there is growing evidence that paracetamol, is sometimes used outside approved indications or abused (i.e. used for non-medical reasons). This review highlights the need for enhanced pharmacovigilance and surveillance of non-medical paracetamol use and raising general public awareness of its potential dangers especially in higher than recommended doses. [ABSTRACT FROM AUTHOR]

Objective. To determine the risk: benefit of paracetamol combined with caffeine in the short-term management of acute pain conditions. Design. Database searches were conducted to identify double-blind trials comparing paracetamol/caffeine with paracetamol alone (benefit analysis) and any data pertaining to hepatotoxicity of paracetamol when combined with caffeine (risk analysis). Interventions. Paracetamol/caffeine (1,000 mg/130 mg) vs paracetamol (1,000 mg) alone. Outcome Measures. Assessment of benefit has been derived by meta-analysis. Information on the pain condition and number of patients studied, dosing regimen, study design and analgesic outcome measures (total pain relief scores) was extracted and dichotomous outcomes were obtained by calculating the number of patients in each treatment group who achieved at least 50% of the maximum total pain relief score. Assessment of risk has been made by appraisal of the literature. Results. Eight studies from four papers provided sufficient quantitative data for satisfactory meta-analysis. The relative benefit (of achieving at least 50% pain relief) of paracetamol/caffeine vs paracetamol alone was 1.12 (95% Confidence Interval 1.05–1.19) across a number of acute pain states (dysmenorrhoea, headache, post-partum pain, and dental pain). Review of the effects of the combination of paracetamol and caffeine on the liver revealed no compelling data to suggest a clinically meaningful increase in hepatotoxicity with use of paracetamol/caffeine combinations. Conclusions. Paracetamol/caffeine (1,000 mg/130 mg) is effective and safe for use in acute management of pain. The hepatotoxicity of overdoses of paracetamol results from its oxidative metabolism, caffeine does not produce any increase in oxidative metabolism of therapeutic concentrations of paracetamol. [ABSTRACT FROM AUTHOR]

Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996–2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r  = 0.59) than internalizing (r  = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%–40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%–19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence. [ABSTRACT FROM AUTHOR]

Objectives Improper usage of acetaminophen (APAP) leads to morbidity and also mortality secondary to liver damage. Ginseng could suppress APAP-induced hepatotoxicity and ginsenoside Rg3 is a kind of major component in ginseng against liver damage. Herein, we intended to estimate the beneficial function and molecular mechanism of Rg3 on APAP-caused hepatotoxicity and identified hepatoprotection. Methods A total of 50 C57BL/6J mice were divided into five random groups, and each contains 10 mice as the control, acetaminophen (350 mg/kg) and Rg3 (5, 10 and 20 mg/kg) + acetaminophen (350 mg/kg) groups. These mice were intragastric administration a single dose of acetaminophen by oral treatment behind pre-administered with several doses of ginsenoside Rg3 for six hours. Key findings According to our data, the injection of APAP (350 mg/kg) enhanced the basal levels of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and lactic dehydrogenase. However, these abnormal added were alleviated by Rg3. Moreover, Rg3 treatment obviously relieved APAP-caused inflammation and oxidant in liver tissues. The depletion of glutathione, glutathione peroxidase, total antioxidant capacity and generation of malondialdehyde induced by APAP treatment were reduced by Rg3. By H&E staining, Rg3 effectively reduced APAP-caused apoptosis and inflammatory infiltration. Moreover, Rg3 attenuated APAP-caused hepatic damage in part by regulating the pro-inflammatory and anti-inflammatory cytokines. Moreover, we found that Rg3 could bind to NLRP3 suggesting the anti-inflammatory effects of Rg3 by molecular docking study. Conclusions In summary, Rg3 showed hepatic protective function in APAP-induced hepatotoxicity as evidenced by a reduction of the oxidant and the inflammatory reply, relieve of hepatocellular damage, showing potential in Rg3 as a potential therapeutic medicine to prevent hepatic injury. [ABSTRACT FROM AUTHOR]

Taraxacum syriacum (TS) with natural antioxidant and pharmacological activities may be considered for treatment of oxidative stress induced by acetaminophen (APAP). The aim of this study was to evaluate the ameliorative effects of the ethanol extract of TS root against hepatorenal toxicity induced by APAP in comparison to N-acetylcysteine (NAC) as a standard drug. Thirty male Wistar rats were randomly divided into five groups. Control group; APAP (1 g/kg) group; APAP–NAC (160 mg/kg) group and APAP-TS100 and APAP-TS200 groups: APAP plus 100 and 200 mg/kg of TS extract, respectively. After 7 days treatment, serum and liver and kidney tissues were prepared and evaluated. TS extract ameliorated the increased lipid peroxidation level and decreased antioxidant enzymes activities and glutathione level in liver and kidney of APAP-treated rats. Moreover, treatment with the TS extract caused significant reduction in the histopathological damages and high levels of serum biochemical markers of hepatic and renal functions after APAP treatment. This study suggests that the extract of TS roots has dose-dependent ameliorative effect against APAP-induced oxidative damage in liver and kidney due to its free radical scavenging and antioxidant properties. The overall efficacy of the extract at 200 mg/kg dose is comparable with NAC. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to couple fused deposition modelling 3D printing with melt extrusion technology to produce core-shell-structured controlled-release tablets with dual-mechanism drug-release performance in a simulated intestinal fluid medium. Coupling abovementioned technologies for personalized drug delivery can improve access to complex dosage formulations at a reasonable cost. Compared with traditional pharmaceutical manufacturing, this should facilitate the following: (1) the ability to manipulate drug release by adjusting structures, (2) enhanced solubility and bioavailability of poorly water-soluble drugs and (3) on-demand production of more complex structured dosages for personalized treatment. Methods Acetaminophen was the model drug and the extrusion process was evaluated by a series of physicochemical characterizations. The geometries, morphologies, and in vitro drug-release performances were compared between directly compressed and 3D-printed tablets. Key findings Initially, 3D-printed tablets released acetaminophen more rapidly than directly compressed tablets. Drug release became constant and steady after a pre-determined time. Thus, rapid effectiveness was ensured by an initially fast acetaminophen release and an extended therapeutic effect was achieved by stabilizing drug release. Conclusions The favourable drug-release profiles of 3D-printed tablets demonstrated the advantage of coupling HME with 3D printing technology to produce personalized dosage formulations. [ABSTRACT FROM AUTHOR]

Background Data on drug utilisation patterns in nursing home populations is scarce. We aimed to describe drug use patterns in Danish nursing home residents. Methods We established a cohort of 5,179 individuals (63% women; median age of 84 years) admitted into 94 nursing homes across Denmark during 2015–2017. Data on prescription drug use and other census data were obtained from the nationwide Danish health registries. Results The total number of drug classes filled increased from a median of 6 drugs (interquartile range [IQR] 3–9) at 18–24 months before nursing home admission to a median of 8 drugs (IQR 6–11) just after admission, with the most common drug classes comprising paracetamol (61%), platelet inhibitors (41%), proton pump inhibitors (34%), statins (33%) and potassium supplements (31%). The incidence rate of new drug treatments increased from 21 new treatments/100 residents/month at 12–24 months before admission to a peak of 71 new treatments/100 residents/month in the month prior to admission, while it levelled off to about 34 new treatments/100 residents/month after 6–9 months. The drug classes primarily responsible for this peak were laxatives, antibiotics and analgesics. The largest absolute increases were seen for laxatives (53%), paracetamol (43%) and antidepressants (36%), all showing a marked increase up to and following admission. A high proportion of residents remained on therapy in the 3-year period following admission, with users of antidepressants and antidementia drugs being most persistent. Conclusion Nursing home admission is associated with an increase in use of both predominantly preventive and non-preventive drug classes. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy is a pathophysiological complication of acute liver failure, which may be triggered by hepatotoxic drugs such as acetaminophen (APAP). Although APAP is safe in therapeutic concentration, APAP overdose may induce neurotoxicity, which is mainly associated with oxidative stress. Caffeine is a compound widely found in numerous natural beverages. However, the neuroprotective effect of caffeine remains unclear during APAP intoxication. The present study aimed to investigate the possible modulatory effects of caffeine on brain after APAP intoxication. Mice received intraperitoneal injections of APAP (250 mg/kg) and/or caffeine (20 mg/kg) and, 4 h after APAP administration, samples of brain and blood were collected for the biochemical analysis. APAP enhanced the transaminase activity levels in plasma, increased oxidative stress biomarkers (lipid peroxidation and reactive oxygen species), promoted an imbalance in endogenous antioxidant system in brain homogenate and increased the mortality. In contrast, APAP did not induce dysfunction of the mitochondrial bioenergetics. Co-treatment with caffeine modulated the biomarkers of oxidative stress as well as antioxidant system in brain. Besides, survival assays demonstrated that caffeine protective effects could be dose- and time-dependent. In addition, caffeine promoted an increase of mitochondrial bioenergetics response in brain by the enhancement of the oxidative phosphorylation, which could promote a better energy supply necessary for brain recovery. In conclusion, caffeine prevented APAP-induced biochemical alterations in brain and reduced lethality in APAP-intoxicated mice, these effects may relate to the preservation of the cellular antioxidant status, and these therapeutic properties could be useful in the treatment of hepatic encephalopathy induced by APAP intoxication. [ABSTRACT FROM AUTHOR]

Medicines are usually prescribed for repeated use over shorter or longer times. Unfortunately, repeated-dose animal toxicity studies do not correlate well with observations in man. As emphasized by the '3Rs' and the desire to phase-out animal research, in vitro models are needed. One potential approach uses clinostat-cultured 3D HepG2--C3A liver-mimetic spheroids. They take 18 days to recover in vivo physiological functionality and reach a metabolic equilibrium, which is thereafter stable for a year. Acute and chronic repeated-dose studies of six drugs (amiodarone, diclofenac,metformin, phenformin, paracetamol and valproic acid) suggest that spheroids are more predictive of human in vivo toxicity than either 2D-cultured HepG2 cells or primary human hepatocytes. Repeated non-lethal treatment results in a clear response and return to equilibrium. Mitochondrial toxic compounds can be identified using a galactose-based medium. Some drugs induced a protective (or stress) response that intensifies after the second treatment. This 3D spheroid model is inexpensive, highly reproducible and well-suited for the determination of repeated-dose toxicity of compounds (naturally or chemically synthesized). [ABSTRACT FROM AUTHOR]

Present study was planned to investigate the ameliorative effect of silver nanoparticles (AgNPs) on acetaminophen-induced nephrotoxicity. Our results demonstrate that therapy of AgNPs at three different doses (50, 100 and 150 μg/kg once only) prevented the acetaminophen (2 g/kg once only) induced acute renal toxicity. AgNPs treated animals also show less intensity in the histological alterations in kidneys and corroborating the results of analysis of serum urea and creatinine. In addition, AgNPs therapy prevented the acetaminophen-induced oxidative stress, which was confirmed by the alleviated lipid peroxidation, enhanced renal reduced glutathione content and restored enzymatic activities of superoxide dismutase, catalase and adenosine triphosphatase in kidney. Thus, our results demonstrate a possible protective potential of AgNPs on renal toxicity induced by acetaminophen. This study will definitely lead to the development of therapeutic drug against nephrotoxicity, after further clinical and preclinical studies. [ABSTRACT FROM AUTHOR]

Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl- p -aminophenol, paracetamol) overdose is a significant clinical problem in most western countries. The only clinically approved antidote is N-acetylcysteine (NAC), which promotes the recovery of hepatic GSH. If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl- p -benzoquinone imine. More recently, it was shown that NAC can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite and can support mitochondrial bioenergetics. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP is a potent c-Jun N-terminal kinase inhibitor expanding its therapeutic window. Calmangafodipir (CMFP) is a SOD mimetic, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin and methylene blue were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities, Nrf2-dependent gene induction and autophagy activation by herbal medicine components are being evaluated. However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds. Nevertheless, based on recent studies, 4-methylpyrazole and calmangafodipir have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose. [ABSTRACT FROM AUTHOR]

The developmental origins of health and disease (DOHaD) model promises a greater understanding of early development but has left unresolved the balance of risks and benefits to offspring of medication use during pregnancy. Masarwa et al. (Am J Epidemiol. 2018;187(8):1817–1827) conducted a meta-analysis of the association between in utero acetaminophen exposure and risks of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A challenge of meta-analyzing results from observational studies is that summary measures of risk do not correspond to well-defined interventions when the individual studies adjusted for different covariate sets, which was the case here. This challenge limits the usefulness of observational meta-analyses for inferences about etiology and treatment planning. With that limitation understood, Masarwa et al. reported a 20%–30% higher risk of ADHD and ASD following prenatal acetaminophen exposure. Surprisingly, most of the original studies did not report diagnoses of ADHD or ASD. As a result, their summary estimates of risk are not informative about children's likelihood of ADHD and ASD diagnoses. The long-term promise of DOHaD remains hopeful, but more effort is needed in the short-term to critically evaluate observational studies suggesting risks associated with medications used to treat conditions during pregnancy that might have adverse consequences for a developing fetus. [ABSTRACT FROM AUTHOR]

We present the case of a 71-year-old female treated for infective endocarditis with flucloxacillin and paracetamol. Her clinical course became complicated by a blood-gas demonstrating a raised anion gap metabolic acidosis. The patient was diagnosed with pyroglutamic metabolic acidosis. This is a rare interaction between high dose flucloxacillin and paracetamol, and is an important complication to recognize. [ABSTRACT FROM AUTHOR]

The article describes the case of a -year-old Caucasian man who developed transient hip osteoporosis in correlation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. He was tested positive for SARS-CoV2 and was given a short course of ibuprofen and acetylcysteine. Ibuprofen and paracetamol were also given to address worsening hip pain. Magnetic resonance imaging of the pelvis was done and a diagnosis of transient osteoporosis of the hip was established.

The article discusses a National Council for Prescription Drug Programs (NCPDP) white paper "NCPDP Recommendations for Improved Prescription Container Labels for Medicines Containing Acetaminophen." The paper that names of active ingredients in prescription drugs should be spelt out and "APAP" be replaced with "acetaminophen" on drug labels. The article also mentions that the FDA has set January 14, 2014 as a deadline for companies to decrease acetaminophen content in dosage units of drugs.

The article presents several abstracts on geriatrics which include the development of a model in monitoring intra-cellular reactive oxygen species (ROS) activities in lymphocytes from adult and old subjects, anticipated lifespan of active and sedentary people, and the use of telephone health information service to improve the treatment and diagnosis of osteoporosis post fragility fracture.

Background Theoretically, root resorption could be modulated by any medication taken that exhibits possible effects on the implicated molecular pathways. Objectives To systematically investigate and appraise the quality of the available evidence from animal studies, regarding the effect of commonly prescribed systemic medication on root resorption associated with orthodontic tooth movement. Search methods Search without restrictions in eight databases (PubMed, Central, Cochrane Database of Systematic Reviews, SCOPUS, Web of Science, Arab World Research Source, ClinicalTrials.gov, ProQuest Dissertations and Theses Global) and hand searching until April 2018 took place. One author developed detailed search strategies for each database that were based on the PubMed strategy and adapted accordingly. Selection criteria Controlled studies investigating the effect of systemic medications on root resorption associated with orthodontic tooth movement. Data collection and analysis Following study retrieval and selection, relevant data were extracted and the risk of bias was assessed using the SYRCLE's Risk of Bias Tool. Results Twenty-one studies were finally identified, most of which at unclear risk of bias. Root resorption was shown to increase in Vitamin C treated animals in comparison with the control group, whereas a comparative decrease was noted after the administration of the alendronate, ibuprofen, growth hormone, low doses of meloxicam, simvastatin, lithium chloride and strontium ranelate. No difference was noted for acetaminophen, aspirin, fluoxetine, atorvastatin, misoprostol, zoledronic acid and zinc. Finally, inconsistent effects were observed after the administration of celecoxib, prednisolone and L-thyroxine. The quality of the available evidence was considered at best as low. Conclusions The pharmaceutical substances investigated were shown to exhibit variable effects on root resorption. Although the overall quality of evidence provides the clinician with a cautious perspective on the strength of the relevant recommendations, good practice would suggest that it is important to identify patients consuming medications and consider the possible implications. Registration PROSPERO (CRD42017078208) [ABSTRACT FROM AUTHOR]

Ascorbic acid (ASC), paracetamol (PAR) and guaifenesin (GUF) are co-formulated together as analgesic and expectorant effervescent powder. This work describes a selective stability indicating HPTLC-densitometric method which is the first developed stability indicating one for chromatographic separation of the three studied drugs in presence of paracetamol toxic impurity [4-aminophenol (4-AP)] and guaifenesin related substance [impurity, (guaiacol) (GUC)]. The chromatographic separation was carried out on HPTLC 60F254 plates using chloroform–acetone–trifluoroacetic acid (6.5:3.5:0.30, by volume) as a developing system with UV detection at 254 nm. Factors affecting chromatographic separation have been optimized and good separation was obtained between the studied components where (ASC R f = 0.05, 4-AP R f = 0.12, GUF R f = 0.24, PAR R f = 0.41 and GUC R f = 0.56). Method validation has been performed according to ICH guidelines and linearity was achieved in the range of 0.4–2.4, 0.4–2.8 and 4–15 μg/band for ASC, PAR and GUF, respectively. In order to evaluate the developed method it was applied for determination of the cited drugs in G.C.Mol® effervescent powder and the obtained results were statistically compared with those obtained by applying the reported HPLC method using Student's t - and F -tests where no significant difference was observed. The developed method has the advantages over the reported HPLC one of being more sensitive and selective which permit its application in quality control analysis of the cited their in presence of drug impurities. [ABSTRACT FROM AUTHOR]

This study explored the association between exposure to acetaminophen during pregnancy and pubertal development using data from 15,822 boys and girls in the longitudinal Puberty Cohort, nested within the Danish National Birth Cohort. Use of acetaminophen was reported 3 times during pregnancy and 6 months postpartum. In total, 54% of mothers indicated use at least once during pregnancy. Between 2012 and 2017, sons and daughters provided information on a wide range of pubertal milestones—including Tanner stages, axillary hair growth, and age at menarche or voice break and first ejaculation—every 6 months from 11 years of age until full sexual maturation. Data were analyzed using a regression model for interval-censored data, providing adjusted mean monthly differences in age at attaining the pubertal milestones according to intrauterine cumulative (weeks) and trimester-specific acetaminophen exposure. Our results suggested a tendency towards slightly earlier attainment of almost all studied markers of female pubertal development with increasing number of weeks of exposure (i.e. about 1.5–3 months earlier age at pubic hair, axillary hair, and acne development comparing unexposed with those prenatally exposed for more than 12 weeks). Male pubertal development had no strong association with acetaminophen exposure. [ABSTRACT FROM AUTHOR]

Background: Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D.Methods: Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D.Results: Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D.Conclusions: Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases. [ABSTRACT FROM AUTHOR]

Background Intentional drug overdose (IDO) is the most common form of hospital-treated self-harm, yet no national study has systematically classified the range of drugs involved using a validated system. We aimed to determine the profile of patients engaging in overdose, to identify drugs frequently used and to quantify the contributions of multiple drug use and alcohol involvement. Methods Between 2012 and 2014, the National Self-Harm Registry, Ireland recorded 18 329 presentations of non-fatal IDO to Irish emergency departments. Information on demographic and overdose characteristics were obtained. Drugs were categorized using the Anatomical Therapeutic Chemical classification system. Results Analgesics (32.4%), antidepressants (21.9%), anxiolytics (21.2%) and hypnotics and sedatives (21.0%) were the most frequently used drugs types involved in overdose. Presentations involving analgesic and antidepressant medication were more common for females whereas males more often took illegal, anxiolytic and hypnotic and sedative drugs. Overdoses with drugs other than those which affect the nervous system were identified, including musculoskeletal drugs, taken in 12.0% of presentations. Paracetamol was the most frequently used drug, particularly among females (32.0%) and persons under 25 years (36.2%). Alcohol was most often present in overdoses involving anxiolytics and illegal drugs. Multiple drug use was a factor in almost half (47.1%) of presentations. Conclusions People who engage in IDO frequently take prescription only or sales restricted drugs, often involving alcohol and/or multiple drug use. These findings highlight the importance of addressing drug and alcohol misuse, potential inappropriate prescribing and the enforcement of legislation restricting specific drug sales. [ABSTRACT FROM AUTHOR]

A simple, sensitive and rapid micellar liquid chromatographic method was developed and validated for simultaneous determination of four drugs, namely, paracetamol (PAR), tizanidine (TZD), aceclofenac (ACF) and nimesulide (NMD). Good chromatographic separation was achieved using Cyano column and micellar mobile phase consisting of 120mM sodium dodecyl sulfate, 25mM phosphate buffer and 10% (V/V) butanol. The pH was adjusted to three using phosphoric acid. The total retention time was below 10 min. The analysis was performed at a flow rate of 1 mL/min and a column temperature of 40°C with direct UV detection at 230 nm. Diclofenac sodium was used as the internal standard. The proposed method was validated according to the ICH guidelines and was successfully applied to the analysis of these drugs in their tablet dosage forms with high accuracy. Limits of detection were found to be 0.03, 0.07, 0.033 and 0.11 µg/mL for PAR, ACF, TZD and NMD, respectively. The high sensitivity of developed method permitted its application to the in-vitro determination of the cited drugs in spiked human plasma and urine samples, and the obtained results were satisfactory. However, PAR could not be determined in spiked human urine because its peak overlapped with that of the urine peak. [ABSTRACT FROM AUTHOR]

Hepatotoxicity due to acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Chlorogenic acid (CGA), a dietary polyphenol, was reported to prevent APAP-induced liver injury in our previous studies. This study aims to investigate the protection provided by CGA against APAP-induced hepatotoxicity via focusing on nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular regulated protein kinases (ERK)1/2. CGA prevented APAP-induced oxidative liver injury and enhanced Nrf2 activation in mice and in hepatocytes in vitro. CGA-provided the protection against APAP-induced hepatotoxicity was diminished after the application of Nrf2 siRNA in vitro and Nrf2 knockout mice in vivo. CGA enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), and their inhibitors reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. Molecular docking results indicated the potential interaction of CGA with Nrf2 binding site in Kelch-like ECH-associating protein-1 (Keap1). CGA decreased the expression of protein phosphatases including PP2A subunit A (PP2A-A) and PP5, and induced the sustained ERK1/2 phosphorylation. Moreover, ERK1/2 inhibitors (U0126 and PD98059) and ERK2 siRNA abrogated CGAinduced Nrf2 phosphorylation and its subsequent transcriptional activation, and also reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. These results suggest that CGA protects against APAP-induced hepatotoxicity by activating Nrf2 antioxidative signaling pathway via blocking the binding of Nrf2 to its inhibitor protein Keap1, and ERK1/2 plays a critical role in regulating CGA-induced Nrf2 transcriptional activation. CGA is a promising therapeutic agent for the detoxification of APAP-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Objectives Excessive exposure to acetaminophen ( APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 ( CYP) isoforms, mainly CYP2E1. A number of naturally occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects and to evaluate possible human applicability. Methods Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase ( UGT) isoforms and of APAP glucuronidation and sulfation. The experimental model was based on in-vitro metabolism by human liver microsomes, using isoform-specific substrates. Key findings Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency towards CYP1A2 and CYP2C8. However, 50% inhibitory concentrations ( IC50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation. Conclusions Inhibition of human CYP activity by luteolin and quercetin occurred with IC50 values exceeding customary in-vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Objectives To test the ability of a multicriteria decision analysis ( MCDA) model to incorporate disparate data sources of varying quality along with clinical judgement in a benefit-risk assessment of six well-known pain-relief drugs. Methods Six over-the-counter ( OTC) analgesics were evaluated against three favourable effects and eight unfavourable effects by seven experts who specialise in the relief of pain, two in a 2-day facilitated workshop whose input data and judgements were later peer-reviewed by five additional experts. Key findings Ibuprofen salts and solubilised emerged with the best benefit-risk profile, followed by naproxen, ibuprofen acid, diclofenac, paracetamol and aspirin. Conclusions Multicriteria decision analysis enabled participants to evaluate the OTC analgesics against a range of favourable and unfavourable effects in a group setting that enabled all issues to be openly aired and debated. The model was easily communicated and understood by the peer reviewers, so the model should be comprehensible to physicians, pharmacists and other health professionals. [ABSTRACT FROM AUTHOR]

Objective This research aims to assess the knowledge of pharmacists regarding acetaminophen dosing, risks, products containing acetaminophen and counselling practices. Methods Descriptive, cross-sectional study was conducted in two private tertiary care facilities (Northwest General Hospital & Research Centre and Rehman Medical Institute Pvt limited) during the month of April 2015 in Peshawar, Khyber Pakhtunkhwa, Pakistan. These healthcare facilities were chosen based on the view that pharmacists in these institutions were conducting their professional duties of dispensing and patient counselling. Pharmacists ( n = 82) working in these two hospitals were asked to participate in a survey. A questionnaire derived from published literature, containing 16 items regarding the acetaminophen was designed to evaluate their knowledge on acetaminophen. Questions were formatted as multiple choices, yes/no, true/false, unsure and short answer. Key findings Of 82 pharmacists, 68 completed and returned the questionnaire with a response rate of 82.9%. Only 70.6% of the respondents identified the maximum daily dose of acetaminophen. Almost 85.2% of the pharmacists correctly identified hepatotoxicity as the primary toxicity associated with acetaminophen. 89.6% of the pharmacists correctly identified the potential risk factors for acetaminophen-induced hepatotoxicity. About 95.5% respondents correctly identified Tramapar (Efroze Chemical Industries Pakistan Limited, Karachi- 74900, Pakistan) as containing acetaminophen. Only 47% of pharmacists reported that they provide specific instructions and precautions when dispensing acetaminophen. Conclusion Our study revealed deficiencies in pharmacist knowledge regarding acetaminophen recognition, dosing recommendations and potential for toxicity. The findings emphasize the need for an increasing pharmacist awareness of unintentional acetaminophen toxicity and acetaminophen-related problems by acquiring sufficient knowledge regarding drug-induced diseases and patient counselling regarding drug use. [ABSTRACT FROM AUTHOR]

Overdose of acetaminophen (APAP) causes severe liver injury and even acute liver failure in both mice and human. A recent study by Kim et al. (2015, Metformin ameliorates acetaminophen hepatotoxicity via Gadd45b-dependent regulation of JNK signaling in mice. J. Hepatol. 63, 75-82) showed that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. However, its exact protective mechanism has not been well clarified. To investigate this, C57BL/6J mice were treated with 400 mg/kg APAP and 350 mg/kg metformin was given 0.5h pre- or 2h post-APAP. Our data showed that pretreatment with metformin protected against APAP hepatotoxicity, as indicated by the over 80% reduction in plasma alanine aminotransferase (ALT) activities and significant decrease in centrilobular necrosis. Metabolic activation of APAP, as indicated by glutathione depletion and APAP-protein adducts formation, was also slightly inhibited. However, 2h post-treatment with metformin still reduced liver injury by 50%, without inhibition of adduct formation. Interestingly, neither pre- nor post-treatment of metformin inhibited c-jun N-terminal kinase (JNK) activation or its mitochondrial translocation. In contrast, APAP-induced mitochondrial oxidant stress and dysfunction were greatly attenuated in these mice. In addition, mice with 2 h post-treatment with metformin also showed significant inhibition of complex I activity, which may contribute to the decreased mitochondrial oxidant stress. Furthermore, the protection was reproduced in JNK activation-absent HepaRG cells treated with 20mM APAP followed by 0.5 or 1mM metformin 6h later, confirming JNK-independent protection mechanisms. Thus, metformin protects against APAP hepatotoxicity by attenuating the mitochondrial oxidant stress and subsequent mitochondrial dysfunction, and may be a potential therapeutic option for APAP overdose patients. [ABSTRACT FROM AUTHOR]

Background: Previous studies showed that children exposed to paracetamol during fetal life might have an increased risk of neurodevelopmental problems. Since paracetamol is one of the most commonly used medications during pregnancy, even small increases in the risk of neurodevelopmental problems may have considerable implications for public health.Methods: Using data from the Norwegian Mother and Child Cohort Study, we applied propensity score (PS) matching to examine associations between prenatal paracetamol exposure and neurodevelopmental problems among children at 18 months of age. Paracetamol use was classified into short-term (< 28 days) and long-term (≥ 28 days) of exposure.Results: Of the 51 200 pregnancies included in our study, 40.5% of mothers ( n  = 20 749) used paracetamol at least once during pregnancy. In the PS-matched analyses, long-term paracetamol exposure during pregnancy was associated with communication problems [odds ratio (OR): 1.38, 95% confidence interval (CI) 0.98-1.95) and delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70). We did not observe increased risks after short-term exposure. Sensitivity analyses for several indications showed similar effects as the PS-matched analyses, suggesting no confounding by indication.Conclusion: Long-term exposure to paracetamol in utero was associated with modestly increased risks of motor milestone delay and impaired communication skills among children at 18 months. Caution is warranted when considering long-term use of paracetamol during pregnancy; however, women with severe pain conditions should not be deprived of appropriate pharmacotherapy. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen is extensively used during pregnancy. But there is a lack of population-representative cohort studies evaluating its effects on a range of neuropsychological and behavioural endpoints. We aimed to assess whether prenatal exposure to acetaminophen is adversely associated with neurodevelopmental outcomes at 1 and 5 years of age.Methods: This Spanish birth cohort study included 2644 mother-child pairs recruited during pregnancy. The proportion of liveborn participants evaluated at 1 and 5 years was 88.8% and 79.9%, respectively. Use of acetaminophen was evaluated prospectively in two structured interviews. Ever/never use and frequency of use (never, sporadic, persistent) were measured. Main neurodevelopment outcomes were assessed using Childhood Autism Spectrum Test (CAST), Conner's Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list. Regression models were adjusted for social determinants and co-morbidities.Results: Over 40% of mothers reported using acetaminophen. Ever-exposed offspring had higher risks of presenting more hyperactivity/impulsivity symptoms [incidence rate ratio (IRR) = 1.41, 95% confidence interval (CI) 1.01-1.98), K-CPT commission errors (IRR = 1.10, 1.03-1.17), and lower detectability scores (coefficient β = -0.75, -0.13--0.02). CAST scores were increased in ever-exposed males (β = 0.63, 0.09-1.18). Increased effect sizes of risks by frequency of use were observed for hyperactivity/impulsivity symptoms (IRR = 2.01, 0.95-4.24) in all children, K-CPT commission errors (IRR = 1.32, 1.05-1.66) and detectability (β = -0.18, -0.36-0.00) in females, and CAST scores in males (β = 1.91, 0.44-3.38).Conclusions: Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. These associations seem to be dependent on the frequency of exposure. [ABSTRACT FROM AUTHOR]

Study Question: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)?Summary Answer: Higher urinary paracetamol concentrations among male partners were associated with a longer TTP.What Is Known Already: Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking.Study Design, Size, Duration: This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA.Participants/materials, Setting, Methods: Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other.Main Results and the Role Of Chance: Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously.Limitations, Reasons For Caution: Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders.Wider Implications Of the Findings: If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment.Study Funding/competing Interests: This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. [ABSTRACT FROM AUTHOR]

Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebocontrolled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses the white paper from the National Council for Prescription Drug Programs on the issue of acetaminophen overuse.