Paracetamol poisoning: a population-based study from Iceland.

OBJECTIVE: To examine the incidence and severity of paracetamol poisoning in a population-based cohort in Iceland. A previous study showed a decrease in the incidence during a financial crisis in Iceland, by approximately half (16/100,000 annually). The aims of the study were to assess the incidence and nature of paracetamol poisoning after economic recovery in Iceland and to compare intentional and accidental poisoning. METHODS: Paracetamol serum concentrations were used to identify patients in this retrospective study from 2010-2017. A search was undertaken in laboratory databases for patients with serum paracetamol concentrations, which were grouped by <66 µmol/L (below detection limit) and ≥66 µmol/L. Medical records were reviewed and relevant laboratory and clinical information obtained to determine whether paracetamol poisoning had occurred. RESULTS: Altogether 542 cases of paracetamol poisoning were identified. The mean annual incidence was 27/100,000 (range 22-33). Intentional poisoning was observed in 437/542 (81%) cases, most frequently among females 16-25 years of age. Males ≥65 years were more likely to overdose by accident, which was associated with worse outcomes. Twenty-five (4.6%) patients developed severe paracetamol-induced liver injury and coagulopathy. Overall, six (1.1%) cases were fatal in which paracetamol contributed to the cause of death, with accidental poisoning found in 67% (4/6). CONCLUSIONS: The incidence of paracetamol poisoning has increased in recent years associated with economic recovery in Iceland. Most patients had favourable outcomes. Intentional overdose was most common in young females, whereas accidental overdose was more common in older males and more frequently associated with a fatal outcome.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Application of the thick extract from Maitake mushrooms for correction of metabolic disorders under the paracetamol hepatitis in rats.

It is known that the violation of one or more functions of the liver, where the basic biochemical processes take place, is reflected in the functional state of many organs and systems, causing severe consequences. For the effective treatment of the hepatobiliary system diseases the drugs from fungi and plant materials are promising, the ingredients of which are close to natural metabolites, have different mechanisms of hepatoprotective action and, in general, can have a positive effect on liver function. AIM: The aim of the research was to investigate the hepatoprotective properties of the Maitake mushrooms thick extract in the experiment on rats with paracetamol (acetaminophen)-induced hepatitis. MATERIALS AND METHODS: The study was performed on 60 white male rats weighing 180-210 g and aged 6-6,5 months. Rats were divided into 10 groups, each of which included 6 animals. Acute hepatitis was simulated by acetaminophen intragastrically administering at a dose of 1250 mg/ kg of body weight 1 time per day as a suspension in 2% starch gel solution for 2 days. Correction of the toxic lesions was performed with a thick extract of Maitake mushrooms, which was administered intragastrically 2 hours before the introduction of acetaminophen and daily after the lesion at a dose of 150 mg/kg of body weight. "Silibor" (active basis - silymarin) was chosen as a comparison drug, which was administered according to the same scheme as Maitake extract at a dose of 20 mg/kg of animal body weight. On the 3rd, 7th and 10th days from the onset of the lesion, rats were euthanized using sodium barbamyl. Liver homogenate and blood serum were tested. Blood was taken from the hearts of animals. Endogenous intoxication of animals after the introduction of corrective factors was assessed by the activity of ALT, AST, GGTP, LF and the size of the thymol sample. All changes were confirmed by parametric and nonparametric methods of statistical analysis of the results of the study. RESULTS: The expressed cytolysis of hepatocytes, after administration to rats of toxicant, on the basis of research of the activity of aminotransferases, gamma-glutamyltranspeptidase, alkaline phosphatase and thymol sample size is proved. The results of the experiment were confirmed histologically. The introduction of a thick extract of Maitake mushrooms contributed to the normalization of the studied indicators. CONCLUSIONS: The application of the Maitake mushrooms thick extract as a corrective factor in the simulated acetaminophen hepatitis indicates its hepato-, cytoprotective and antioxidative properties.

Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2.

In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.

Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies.

Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue. We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies. We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons. We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention).The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria.

Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third-trimester paracetamol use: evaluation of the German Embryotox cohort.

OBJECTIVE: Risk of fetotoxicity after paracetamol exposure in the third trimester. DESIGN: Observational cohort study and retrospective case assessment. SETTING: Germany, 2008-2017. POPULATION: Pregnant women exposed to paracetamol. METHODS: Prospectively enrolled third-trimester pregnancies that had been exposed to paracetamol (604) were compared with pregnancies exposed to paracetamol in the first and/or second trimester only (1192). Exclusion criteria were exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) in the second or third trimester. Additionally, the Embryotox 'adverse drug reaction in pregnancy' database was screened for cases of fetotoxicity. MAIN OUTCOME MEASURES: The prenatal study end points focused on narrowing or closure of ductus arteriosus Botalli, late fetal death, and oligohydramnios. The postnatal end points included patent ductus arteriosus (PDA), primary pulmonary hypertension (PPHT), and impaired renal function. RESULTS: In both cohorts, no fetus with intrauterine narrowing or closure of the ductus arteriosus Botalli was reported (0/604 versus 0/1192). Oligohydramnios was diagnosed at a similar frequency in both cohorts: 1.3% (8/604) versus 1.6% (19/1192). There was one stillbirth in the study cohort (1/604, 0.2%) and four stillbirths in the comparison cohort (4/1192, 0.3%). The rates of PDA in neonates were similar: 0.7% (4/615) versus 0.7% (9/1212). PPHT as well as serious postnatal renal disorders were reported once in each cohort. In 12 out of 96 retrospective cases, there were indicators for study end points; however, co-exposure to NSAIDs or complex situations weaken the assumption of paracetamol toxicity. CONCLUSIONS: Fetal cardiovascular or renal toxicity of maternal third-trimester paracetamol use appears to be negligible. TWEETABLE ABSTRACT: Paracetamol use in the third trimester does not seem to be associated with a relevant risk of fetotoxicity.

Risk of hospital admission for liver injury in users of NSAIDs and nonoverdose paracetamol: Preliminary results from the EPIHAM study.

PURPOSE: The SALT study found similar per-user risks of acute liver failure (ALF) leading to transplantation (ALFT) between NSAIDs and a threefold higher risk in nonoverdose paracetamol (NOP) users. The objective of EPIHAM was to identify the risks of hospital admission for acute liver injury (ALI) associated with NSAIDs and NOP. METHODS: Case-population study in the 1/97 sample of the French population claims database. Acute liver injury was identified from hospital discharge summaries, from 2009 to 2013. Exposure for cases was dispensing of NSAID or NOP resulting in exposure within 30 days before admission. Population exposure was the number of patients using the drugs over the study timeframe and total number of DDD dispensed. RESULTS: Of 63 cases of ALI, 13 had been exposed to NSAIDs and 24 to NOP. Events per million DDD (95% CI) ranged from 0.46 (0.09-1.34) (ketoprofen) to 1.43 (0.04-7.97) (diclofenac combinations), 0.43 (0.23-0.73) all NSAIDs combined, 0.58 (0.37-0.86) for NOP. There was no association with average duration of treatment. Per patient risk ranged from 19.5 (5.31-49.9) (ibuprofen) per million users to 37.2 (19.8-63.6) all NSAIDs combined, 58.0 (37.2-86.3) for NOP. There was a linear relationship between average treatment duration and per-user risk (R2  = 0.51, P < .05 for NSAIDs, R2  = 0.97, P < .01 for NOP). CONCLUSIONS: Risk of hospital admission for ALI with NSAIDs and NOP was similar and indicative of a dose and duration-related effect (pharmacological) effect. Acute liver injury rates were not predictive of ALFT risk.

Impact of medication on protein and amino acid metabolism in the elderly: the sulfur amino acid and paracetamol case.

The optimisation of nutritional support for the growing number of older individuals does not usually take into account medication. Paracetamol (acetaminophen; APAP) is the first intention treatment of chronic pain that is highly prevalent and persistent in the elderly. Detoxification of APAP occurs in the liver and utilises sulfate and glutathione (GSH), both of which are issued from cysteine (Cys), a conditionally indispensable amino acid. The detoxification-induced siphoning of Cys could reduce the availability of Cys for skeletal muscle. Consequently, APAP could worsen sarcopenia, an important component of the frailty syndrome leading to dependency. The present review provides the rationale for the potential pro-sarcopenic effect of APAP then recent results concerning the effect of chronic APAP treatment on muscle mass and metabolism are discussed. The principal findings are that chronic treatments with doses of APAP comparable with the maximum posology for humans can increase the requirement for sulfur amino acids (SAA), reduce Cys availability for muscle, reduce muscle protein synthesis and aggravate sarcopenia in animals. One clinical study is in favour of an enhanced SAA requirement in the older individual under chronic treatment with APAP. Few clinical studies investigated the effect of chronic treatment with APAP combined with exercise, in nutritional conditions that probably did not affect Cys and GSH homeostasis. Whether APAP can aggravate sarcopenia in older individuals with low protein intake remains to be tested. If true, nutritional strategies based on enhancing Cys supply could be of prime interest to cut down the pro-sarcopenic effect of chronic treatment with APAP.

Dietary supplementation with cysteine prevents adverse metabolic outcomes of repeated cures with paracetamol in old rats.

Cysteine (Cys), a conditionally indispensable amino acid, is required for the detoxification of paracetamol (acetaminophen, N-acetyl-para-aminophenol, 4-hydroxy-acetanilide, APAP), a drug of widespread use in older persons. We recently reported that repeated APAP cures could worsen sarcopenia in old rats, likely to be due to the impairment of Cys/GSH homoeostasis. The aim of the study was to evaluate whether a dietary Cys supplementation during APAP cures could improve Cys/GSH homoeostasis and thus preserve skeletal muscle. Male 21·5-month-old Wistar rats received three 2-week-long cures of APAP (1 % of diet) alone or with extra Cys (0·5 % of diet), intercalated with washout periods of 2 weeks (APAP and APAP-Cys groups, respectively). They were compared with untreated control rats (CT group). CT and APAP-Cys groups were pair-fed to the APAP group. Dietary Cys supplementation was efficient to prevent increase in liver mass (P<0·0001), decrease in liver GSH (P<0·0001), increase in blood GSH concentration (P<0·0001), and to some extent, decrease in plasma free Cys concentration (P<0·05), all induced by repeated APAP cures. The addition of Cys to APAP cures decreased plasma alanine transaminase (P<0·05), the fractional synthesis rate of liver proteins (P<0·01), and increased masses of extensor digitorum longus (P<0·01), and soleus (P<0·05), compared with the APAP group. Cys supplementation prevented alteration in Cys/GSH homoeostasis and increased some muscle masses in old rats under repeated cures with a non-toxic dose of APAP.

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period.

Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg-1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice. Copyright © 2017 John Wiley & Sons, Ltd.

"Always paracetamol, they give them paracetamol for everything": a qualitative study examining Eastern European migrants' experiences of the UK health service.

BACKGROUND: The enlargement of the European Union since 2004 has led to an increase in the number of Eastern European migrants living in the UK. The health of this group is under-researched though some mixed evidence shows they are at higher risk of certain physical health conditions such as heart attacks, strokes, HIV and alcohol use and have poorer mental health. This is compounded by poor or insecure housing, low pay, isolation and prejudice. We aimed to understand the health needs and health service experiences of the Eastern European population in a town in Northern England. METHODS: Five semi structured one-to-one and small group interviews and five focus groups were conducted with 42 Eastern European participants between June and September 2014. The majority of participants were Polish and other participants were from Belarus, Hungary, Latvia, Russia, Slovakia and Ukraine. The data were analysed using thematic framework analysis. RESULTS: Key findings included a good understanding the UK health service structure and high registration and use of general practice/primary care services. However, overall, there were high levels of dissatisfaction, frustration and distrust in General Practitioners (GP). The majority of participants viewed the GP as unhelpful and dismissive; a barrier to secondary/acute care; reluctant to prescribe antibiotics; and that GPs too often advised them to take paracetamol (acetaminophen) and rest. CONCLUSIONS: Overwhelmingly participants had strong opinions about access to primary care and the role of the general practitioners. Although the design of the UK health service was well understood, participants were unhappy with the system of GP as gatekeeper and felt it inferior to the consumer-focused health systems in their country of origin. More work is needed to promote the importance of self-care, reduce antibiotic and medication use, and to increase trust in the GP.

Population pharmacokinetic-pharmacodynamic modelling to describe the effects of paracetamol and N-acetylcysteine on the international normalized ratio.

Paracetamol is one of the most common pharmaceutical agents taken in self-poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N-acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross-over clinical trial. A population pharmacokinetic-pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13-71 years). A one-compartment model with first-order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 µmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.

A Case Report of Cefixime, Paracetamol, and Nimesulide Induced Toxic Epidermal Necrolysis in a Woman with Dengue Infection without any Other Associated Comorbidities.

BACKGROUND: Toxic Epidermal Necrolysis (TEN) is a rare, acute, and life-threatening mucocutaneous disease that occurs after the administration of certain drugs, resulting in extensive keratinocyte cell death, skin involvement at the dermal-epidermal junction, and extensive bullous skin eruptions and sloughing. Many published case reports have observed the presence of fever with a viral infection, drug, and/or genetic association as a possible trigger for TEN but associated with other comorbidities. Physicians still struggle to predict which individuals could be predisposed to TEN. The case report that we present had a history of multiple drug intake and fever due to dengue virus infection but was not associated with any other comorbidity. CASE PRESENTATION: We present an unusual case of a 32-year-old woman of Western Indian origin who had developed dengue infection and suffered toxic epidermal necrolysis following a five-day course of a third-generation cephalosporin antibiotic, cefixime and a three-day course of 2 analgesic drugs, paracetamol (acetaminophen), and nimesulide, with the adverse event occurring on the fifth day of the dengue infection. The offending drugs were stopped, and patient survived with supportive management and hydration. CONCLUSION: The presence of comorbidities may not always be the triggering factor for TEN, though it can affect patient outcomes. Rational drug use is always recommended for patient care. Further research is required to understand the pathomechanism behind the viral-drug-gene interaction.

Exploring public knowledge and perceptions regarding per os OTC pain-relieving medications: the case of paracetamol (acetaminophen).

BACKGROUND: Over-the-counter medications (OTC) are safe and effective when patients follow the patient's information leaflet (PIL) instructions and/or the instructions given by healthcare professionals (HCPs). However, OTC medications could be harmful and unsafe when individuals do not follow the given instructions and/or when their understanding about the proper use of OTC medications is incorrect. This study aimed to investigate the knowledge and perceptions of people regarding paracetamol use in the Republic of Cyprus. METHODS: This cross-sectional study, which belongs to quantitative research methods, included participants visiting community pharmacies in the following three cities of the Republic of Cyprus: Nicosia, Limassol and Larnaca. Participation in the study was voluntary and anonymous. Participants responded to the survey-based questionnaire, which concerned their knowledge and views on paracetamol use. After the data collection, responses were tabulated and analysed statistically. RESULTS: The original compound was shown to be more well-known compared to generics. A notable percentage of respondents-ranging between 13.0% (N = 49) and 29.8% (N = 112)-answered incorrectly that broadly used non-steroidal anti-inflammatory drugs (NSAIDs) contain paracetamol. Furthermore, a remarkable percentage of respondents (71.5%, N = 269 and 50.3%, N = 189, respectively) falsely believed that two widely used combination products in the market of Cyprus (Paracetamol and Hyoscine-N-butylbromide; Paracetamol and Codeine and Caffeine) did not contain paracetamol. A notable percentage of participants (27.6%, N = 100) believed that paracetamol causes low toxicity. More than a third of the respondents (40.2%, N = 149) drink alcohol together with or slightly after consuming paracetamol products. This viewpoint was linked with the participants' attitude towards consuming paracetamol medications after drinking alcohol (OR for consuming alcohol versus not consuming alcohol 0.100, 95% CI 0.044-0.225, p = 0.000). CONCLUSIONS: To the best of our knowledge, this is the first study conducted in the Republic of Cyprus on this topic. Paracetamol is frequently consumed by individuals, both in its generic and original forms. However, the study showed that respondents often misperceive NSAIDs and paracetamol-containing medications. In addition, it is identified that there is a lack of education among people about the safe and effective use of paracetamol, namely, indications, potential side effects, maximum daily dose, alcohol consumption, and the potential risks of hepatotoxicity. The study contributed to the current published literature as it showed that there is a significant public health issue, for which appropriate measures can be established by the respective Authorities of Cyprus.

Characterization and biodegradation of paracetamol by biomass of Bacillus licheniformis strain PPY-2 isolated from wastewater.

Industrialization leads to the entry of diverse xenobiotic compounds into the environment. One such compound is paracetamol (APAP), which is emerging as a pharmaceutical and personal care pollutant (PPCP). In this study, the APAP degrading bacterium was isolated by enrichment culture method from the sewage sample. The microscopy, biochemical, and 16S rRNA gene sequence analyzed the isolate PPY-2, which belongs to Bacillus licheniformis, and GenBank assigned accession number MN744328. Physiological and batch culture degradation studies have indicated that the strain involved in the degradation of APAP. The optimum pH for degradation of the PPY-2 was 7.7, whereas the temperature was 25 °C, agitation speed was 142 rpm, and concentration of APAP was 621 mg/L reported, and the optimum temperatures were 42 °C and 32 °C, respectively. Biomass kinetic was studied at optimal physical conditions, which suggested that the specific growth rate (µ) was 721 mg/L. The GC-MS chromatogram peaks have detected metabolites, viz., oxalic acid, 2-isopropyl-5-methyl cyclohexanone, and phenothiazine. The study confirmed that Bacillus licheniformis strain PPY-2 exhibits metabolic potential to biodegradation APAP and can be further deployed in bioremediation.

Transport Mechanism of Paracetamol (Acetaminophen) in Polyurethane Nanocomposite Hydrogel Patches-Cloisite® 30B Influence on the Drug Release and Swelling Processes.

This article describes the swelling and release mechanisms of paracetamol in polyurethane nanocomposite hydrogels containing Cloisite® 30B (organically modified montmorillonite). The transport mechanism, swelling and release processes of the active substance in nanocomposite matrix were studied using gravimetric and UV-Vis spectroscopic methods. Swelling and release processes depend on the amount of clay nanoparticles in these systems and the degree of crosslinking of PU/PEG/Cloisite® 30B hydrogel nanocomposites. The presence of clay causes, on the one hand, a reduction in free volumes in the polymer matrices, making the swelling process less effective; on the other hand, the high swelling and self-aggregation behavior of Cloisite® 30B and the interactions of paracetamol both with it and with the matrix, cause a change in the transport mechanism from anomalous diffusion to Fickian-like diffusion. A more insightful interpretation of the swelling and release profiles of the active substance was proposed, taking into account the "double swelling" process, barrier effect, and aggregation of clay. It was also proven that in the case of modification of polymer matrices with nanoparticles, the appropriate selection of their concentration is crucial, due to the potential possibility of controlling the swelling and release processes in drug delivery patches.

Acetaminophen metabolism revisited using non-targeted analyses: Implications for human biomonitoring.

The analgesic paracetamol/acetaminophen (N-acetyl-4-aminophenol, APAP) is commonly used to relieve pain, fever and malaise. While sales have increased worldwide, a growing body of experimental and epidemiological evidence has suggested APAP as a possible risk factor for various health disorders in humans. To perform internal exposure-based risk assessment, the use of accurate and optimized biomonitoring methods is critical. However, retrospectively assessing pharmaceutical use of APAP in humans is challenging because of its short half-life. The objective of this study was to address the key issue of potential underestimation of APAP use using current standard analytical methods based on urinary analyses of free APAP and its phase II conjugates. The question we address is whether investigating additional metabolites than direct phase II conjugates could improve the monitoring of APAP. Using non-targeted analyses based on high-resolution mass spectrometry, we identified, in a controlled longitudinal exposure study with male volunteers, overlooked APAP metabolites with delayed formation and excretion rates. We postulate that these metabolites are formed via the thiomethyl shunt after the enterohepatic circulation as already observed in rodents. Importantly, these conjugated thiomethyl metabolites were (i) of comparable diagnostic sensitivity as the free APAP and its phase II conjugates detected by current methods; (ii) had delayed peak levels in blood and urine compared to other APAP metabolites and therefore potentially extend the window of exposure assessment; and (iii) provide relevant information regarding metabolic pathways of interest from a toxicological point of view. Including these metabolites in future APAP biomonitoring methods therefore provides an option to decrease potential underestimation of APAP use. Moreover, our data challenge the notion that the standard methods in biomonitoring based exclusively on the parent compound and its phase II metabolites are adequate for human biomonitoring of a non-persistent chemical such as APAP.

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure.

The metabolic fate, toxicity, and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/l using maintenance doses of 0.5-4 g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype of ALF in using 1H NMR spectroscopy. Increased concentrations of citrate combined with pre-ALF increases in circulating lactate, pyruvate, and alanine in plasma suggest mitochondrial dysfunction and a switch in hepatic energy metabolism to glycolysis in response to APAP treatment. A specific liquid chromatography-tandem mass spectrometry assay was used to quantify APAP and metabolites. The major circulating and urinary metabolite of APAP was the phenolic glucuronide (APAP-G), followed by p-aminophenol glucuronide (PAP-G) formed from N-deacetylated APAP. The PAP produced by N-deacetylation was the likely cause of the methemoglobinemia and kidney toxicity observed in this, and previous, studies in the pig. The phenolic sulfate of APAP, and the glutathione-derived metabolites of the drug were only found as minor components (with the cysteinyl conjugate detected but not the mercapturate). Given its low sulfation, combined with significant capacity for N-deacetylation the pig may represent a poor translational model for toxicology studies for compounds undergoing significant metabolism by sulfation, or which contain amide bonds which when hydrolyzed to unmask an aniline lead to toxicity. However, the pig may provide a useful model where extensive amide hydrolysis is seen for drugs or environmental chemicals in humans, but not in, eg, the rat and dog which are the preclinical species normally employed for safety assessment.

Prescription patterns of analgesics, antipyretics, and non steroidal anti-inflammatory drugs for the management of fever and pain in pediatric patients: a cross-sectional, multicenter study in Latin America, Africa, and the Middle East.

OBJECTIVE: To evaluate the daily practice of pediatricians, physician-perceived reasons for unsatisfactory effects of treatment, and unmet needs in the management of acute pain and/or fever. METHODS: This was a multinational (n=13), multicenter, non interventional, cross-sectional study conducted in Latin America, Africa, and the Middle East in children under 16 years of age with fever (defined as a central body temperature ≥38°C) and/or acute pain (defined as pain lasting ≤6 weeks). Data were collected during a single visit using a structured physician-administered questionnaire and case report forms. RESULTS: A total of 2125 patients were recruited by 178 physicians between September 2010 and September 2011. From the 2117 analyzed patients, 1856 (87.7%) had fever, 705 (33.3%) had acute pain, and 446 (21.1%) had both. Of 1843 analyzed patients with fever, 1516 (82.3%) were previously prescribed a pharmacological treatment for the management of fever concomitantly with a non pharmacological approach, while 1817/1856 patients (97.9%) were currently receiving a prescribed pharmacological treatment for fever. Paracetamol/acetaminophen was the most commonly prescribed antipyretic medication during both previous (70.8%) and current (64.1%) consultations. With regard to acute pain management, 67.2% of the patients received previous and 93.9% received current treatment for pain. The most frequently prescribed analgesic during previous consultations was paracetamol/acetaminophen (53.7%), and the current most commonly prescribed analgesics were non steroidal anti-inflammatory drugs (55.2%). Treatment patterns for patients with both fever and acute pain were similar. Overall, 53.4% of the physicians reported poor treatment compliance as a reason for the unsatisfactory effect of the pain/fever treatment, and the most common unmet need was the availability of new drugs (according to 63.5% of the physicians). CONCLUSIONS: Adequate management of fever was observed; however, due to the complex etiology of pediatric pain, better evaluation and management of pain in pediatrics is necessary.

Increased Paracetamol Bioavailability after Sleeve Gastrectomy: A Crossover Pre- vs. Post-Operative Clinical Trial.

Oral drug bioavailability may be significantly altered after laparoscopic sleeve gastrectomy (LSG), the most popular bariatric procedure worldwide. Paracetamol (acetaminophen) is the post-bariatric analgesic/antipyretic drug of choice. In this work we studied and analyzed the LSG effects on systemic bioavailability and pharmacokinetics of paracetamol after oral administration of solid vs. liquid dosage form. A 4-armed, pharmacokinetic, crossover trial was performed in patients enrolled for LSG. Single paracetamol dose (500 mg), as caplet (n = 7) or syrup (n = 5), was administered before vs. 4-6 months post-LSG. Bioavailability was enhanced after LSG; in the caplet groups, average AUC0-t increased from 9.1 to 18.6 µg·h/mL with AUC0-t difference of 9.5 µg·h/mL (95% CI 4.6-14.5, p = 0.003). Cmax increased from 1.8 (95% CI 1.2-2.5) to 4.2 µg/mL (3.6-4.8) after LSG (p = 0.032). In the syrup groups, AUC0-t increased from 13.4 to 25.6 µg·h/mL, with AUC0-t difference of 12.2 µg·h/mL (95% CI 0.9-23.5, p = 0.049). Cmax changed from 5.4 (95% CI 2.5-8.4) to 7.8 µg/mL (6.1-9.6), and systemic bioavailability was complete (102%) after the surgery. Overall, decreased paracetamol exposure in obesity, with recovery to normal drug levels (caplet) or even higher (syrup) post-LSG, was revealed. In conclusion, attention to paracetamol effectiveness/safety in obesity, and after bariatric surgery, is prudent.