Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment. METHODS: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA. RESULTS: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs. CONCLUSIONS: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease.

INTRODUCTION: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

Using a decision tree algorithm to distinguish between repeated supra-therapeutic and acute acetaminophen exposures.

BACKGROUND: This study aimed to compare clinical and laboratory characteristics of supra-therapeutic (RSTI) and acute acetaminophen exposures using a predictive decision tree (DT) algorithm. METHODS: We conducted a retrospective cohort study using the National Poison Data System (NPDS). All patients with RSTI acetaminophen exposure (n = 4,522) between January 2012 and December 2017 were included. Additionally, 4,522 randomly selected acute acetaminophen ingestion cases were included. After that, the DT machine learning algorithm was applied to differentiate acute acetaminophen exposure from supratherapeutic exposures. RESULTS: The DT model had accuracy, precision, recall, and F1-scores of 0.75, respectively. Age was the most relevant variable in predicting the type of acetaminophen exposure, whether RSTI or acute. Serum aminotransferase concentrations, abdominal pain, drowsiness/lethargy, and nausea/vomiting were the other most important factors distinguishing between RST and acute acetaminophen exposure. CONCLUSION: DT models can potentially aid in distinguishing between acute and RSTI of acetaminophen. Further validation is needed to assess the clinical utility of this model.

Cost-Effectiveness Analysis of Ibuprofen Versus Indomethacin or Paracetamol for the Treatment of Patent Ductus Arteriosus in Preterm Neonates.

This was a first-time evaluation that sought to analyze the cost-effectiveness of oral paracetamol and intravenous (IV) indomethacin as alternatives to ibuprofen for PDA in neonates. Decision-analytic, literature-based, economic simulation models were constructed, to follow up the use and consequences of oral/IV ibuprofen versus IV indomethacin, and oral/IV ibuprofen versus oral paracetamol, as first-line therapies for PDA closure. Model outcomes of interest were "success", defined as PDA closure with/without adverse events, or "failure" due to no response to the first course of treatment, death or premature discontinuation of therapy due to adverse events. Oral ibuprofen is dominant/cost-effective over IV indomethacin in 97.9% of simulated cases, but oral paracetamol was 75.2% dominant/cost-effective over oral ibuprofen. Against IV ibuprofen, IV indomethacin was 55.3% dominant/cost-effective, whereas oral paracetamol was dominant/cost-effective in 98.5% of the cases. Sensitivity analyses confirmed the robustness of the study results. For PDA closure, while IV indomethacin was cost-effective against IV ibuprofen, oral paracetamol was cost-effective against both oral and IV ibuprofen.

Decision tree algorithm can determine the outcome of repeated supratherapeutic ingestion (RSTI) exposure to acetaminophen: review of 4500 national poison data system cases.

This study is aimed at establishing the outcome of RSTI exposure to acetaminophen based on a decision tree algorithm for the first time. This study used the National Poison Data System (NPDS) to conduct a six-year retrospective cohort analysis, which included 4522 individuals. The patients had a mean age of 26.75 ± 16.3 years (1-89). 3160 patients (70%) were females. Most patients had intentional exposure to acetaminophen. Almost all the patients had acetaminophen exposure via ingestion. In addition, 400 (8.8%) experienced major outcomes, 1500 (33.2%) experienced moderate outcomes, and 2622 (58%) of the patients experienced mild ones. The decision tree model performed well in the training and test groups. In the test group, the accuracy was 0.813, precision of 0.827, recall being 0.798, specificity 0.898, and an F1 score 0.80. In the training group, accuracy was 0.831, recall was 0.825, precision was 0.837, specificity was 0.90, and F1 score was 0.829. Our results showed that serum liver enzymes being present at elevated levels (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) greater than 1000 U/L followed by ALT, AST between 100 and 1000 U/L), prothrombin time (PT) prolongation, bilirubin increase, renal failure, confusion, age, hypotension, other coagulopathy (such as partial thromboplastin time (PTT) prolongation), acidosis, and electrolyte abnormality were the effective factors in determining the outcomes in these patients. The decision tree algorithm is a dependable method for establishing the prognosis of patients who have been exposed to RSTI acetaminophen and can be used throughout the patients' hospitalization period.

Efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen for prevention of seizure recurrence during the same fever episode in children with suspected simple febrile seizures.

OBJECTIVE: This study was undertaken to evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS). METHODS: This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children's hospital. Children aged 6 months to 60 months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs. RESULTS: Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (.3-.5 mg/kg for up to two doses) was administered to 88 of 316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk = .29, 95% confidence interval [CI] = .09-.93, p = .03). The adjusted odds ratio of diazepam administration against recurrence was .23 (95% CI = .07-.78, p = .02). None of the patients had a CNS pathology. No severe adverse events occurred, although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs. 18.7%, p = .04). The median medical cost was US $199 (interquartile range [IQR] = 86-244) for the group receiving both medications and US $202 (IQR = 114-242) for the group receiving as-needed acetaminophen alone. SIGNIFICANCE: Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected SFS.

Assessment of embryo morphology following perinatal exposure to aspirin, ibuprofen and paracetamol using whole embryo culture system.

BACKGROUND: Recent evidence from a meta-analysis indicates that maternal prenatal exposure, single or repeated, to non-steroidal anti-inflammatory drugs (NSAIDs) or non-opioid painkillers, is associated with increased risk of cerebral palsy and cognitive-behavioral disorders in offspring. One potential route of action is interference with the neurulation process and hence early brain development. OBJECTIVE: To examine the effect of prenatal exposure to common NSAIDs and non-opioid drugs on neurulation using an in vitro whole embryo culture system. METHODS: Mouse embryos from in-bred Institute of Cancer Research albino strain mice were exteriorized on embryonic day 7.5 and cultured for 48 h in either 1 mL heat-inactivated rat serum + 0.1% dimethyl sulfoxide ("Control") or 1 mL of rat serum supplemented with six increasing concentrations of laboratory-grade aspirin, paracetamol, and ibuprofen ("Experimental"). After culture, embryo morphological and developmental parameters were documented using standardized scoring systems at each dosage concentration. The assessed concentration in rat serum culture ranged from 1.23 to 13.57 mg/mL for aspirin and 0.06-4.93 mg/mL for paracetamol and ibuprofen. The equivalent respective human dosages were 600-6600 mg and 30-2400 mg. RESULTS: Between-group comparisons ("Control" vs "Experimental") and post-hoc pair-wise tests, adjusted for multiple comparisons, indicating no statistically significant effect on crown-rump length (p > .21), head length (p > .28), somite number (p > .25), incidence of absent hindlimb buds (p > .18), yolk sac circulation score (p > .07) and posterior neuropore closure (p > .35) in the aspirin, paracetamol and ibuprofen experiments. All embryos had forelimb buds, closed anterior neuropores and none had neural tube defects. CONCLUSION: This study has demonstrated that there are no safety concerns regarding high-dose aspirin, ibuprofen, and paracetamol on mice's embryonic development.

A systematic assessment of the epidemiologic literature regarding an association between acetaminophen exposure and cancer.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) reviewed the epidemiologic studies of acetaminophen and the data were judged to be "inadequate" to conclude that it is carcinogenic. In 2019 the California Office of Environmental Health Hazard Assessment initiated a review process on the carcinogenic hazard potential of acetaminophen. To inform this review process, the authors performed a comprehensive literature search and identified 136 epidemiologic studies, which for most cancer types suggest no alteration in risk associated with acetaminophen use. For 3 cancer types, renal cell, liver, and some forms of lymphohematopoietic, some studies suggest an increased risk; however, multiple factors unique to acetaminophen need to be considered to determine if these results are real and clinically meaningful. The objective of this publication is to analyze the results of these epidemiologic studies using a framework that accounts for the inherent challenge of evaluating acetaminophen, including, broad population-wide use in multiple disease states, challenges with exposure measurement, protopathic bias, channeling bias, and recall bias. When evaluated using this framework, the data do not support a causal association between acetaminophen use and cancer.

Acute effects of acetaminophen on the developmental, swimming performance and cardiovascular activities of the African catfish embryos/larvae (Clarias gariepinus).

Acetaminophen is a widely used analgesic that has been detected in many water bodies with few reports concerning its potential toxicity to fish. This study sought to assess the developmental, swimming performance and cardiovascular activities of embryo/larvae catfish (Clarias gariepinus) exposed to acetaminophen. The Organization for Economic Development (OECD) Fish Embryo Acute Toxicity Test (OECD 236) was employed. Fertilized embryo were exposed to different concentrations of acetaminophen (0, 0.5, 1, 10 µg/L) for 96 h. Hatching rates of the embryo were observed to decrease with increasing concentrations of acetaminophen. Fish embryo exposed to acetaminophen displayed varying levels of teratogenic effects at different levels of development in a dose-dependent manner. The results also showed a significant (p < 0.05) dose-dependent increase in swimming speed and movement patterns in fish larvae exposed to acetaminophen, with distance travelled in larvae exposed to the highest concentration of acetaminophen (10 µg/L) about eight (8) times the distance travelled by the control larvae, indicating that acetaminophen-induced erratic swimming behaviour in the catfish species. Cardiotoxicity was evident, with a significant reduction in heartbeat rate with increasing concentrations of acetaminophen. The results showed that exposure to acetaminophen resulted in teratogenic, neurotoxic and cardiotoxic effects in embryo/larvae of Clarias gariepinus. The findings suggest that acetaminophen which has recently been detected in many water bodies could potentially impact on survival of aquatic life, especially catfish.

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.

Reduced length of stay and hospitalization costs among inpatient hysterectomy patients with postoperative pain management including IV versus oral acetaminophen.

OBJECTIVE: To compare the outcomes of hysterectomy patients who received standard pain management including IV acetaminophen (IV APAP) versus oral APAP. METHODS: We performed a retrospective analysis of the Premier Database (January 2012 to September 2015) comparing hysterectomy patients who received postoperative pain management including IV APAP to those who received oral APAP starting on the day of surgery and continuing up to the third post-operative day, with no exclusions based on additional pain management. We compared the groups on length of stay (LOS), hospitalization costs, and average daily morphine equivalent dose (MED). The quarterly rate of IV APAP use for all hospitalizations by hospital was used as an instrumental variable in two-stage least squares regressions also adjusting for patient demographics, clinical risk factors, and hospital characteristics. RESULTS: We identified 22,828 hysterectomy patients including 14,811 (65%) who had received IV APAP. Study subjects averaged 50 and 52 years of age, respectively in the IV APAP and oral APAP cohorts and were predominantly non-Hispanic Caucasians (≥60% in both cohorts). Instrumental variable models found IV APAP associated with 0.8 days shorter hospitalization (95% CI: -0.92 to -0.68, p<0.0001) and $2,449 lower hospitalization costs (95% CI: -$2,902 to -$1,996, p<0.0001). Average daily MED trended lower without statistical significance (-1.41 mg, 95% CI: -3.43 mg to 0.61 mg, p = 0.17). CONCLUSIONS: Compared to oral APAP, managing post-hysterectomy pain with IV APAP is associated with shorter LOS and lower total hospitalization costs.

Assessment of biochemical alterations in the neotropical fish species Phalloceros harpagos after acute and chronic exposure to the drugs paracetamol and propranolol.

Over time, many pollutants of anthropogenic origin have caused the contamination of aquatic ecosystems. Among several characteristics, these compounds can reach the trophic chain, causing deleterious interactions with the biota. Pharmaceutical substances can be included in this scenario as emerging contaminants that reach the aquatic environment because of direct human and veterinary usage, and release by industrial effluents, as well as through domestic dumping of surplus drugs. The effects of these compounds on exposed organisms have been studied since the 1990s, but ecotoxicological data for such chemicals are still scarce especially concerning aquatic organisms from tropical regions. Paracetamol and propranolol were selected for this study since they are frequently found in surface waters. Paracetamol is a drug used as analgesic and antipyretic, while propranolol, a ß-blocker, is used in the treatment of hypertension. The objective of this study was to assess the toxic effects of these substances on the neotropical freshwater fish Phalloceros harpagos after acute (96 h) and chronic (28 days) exposures. In order to understand the effects of these drugs on P. harpagos, biochemical markers were selected, including the enzymes involved in oxidative stress, xenobiotic metabolism, and neurotransmission (catalase, glutathione-S-transferase, and cholinesterase activities, respectively). After acute exposure, no significant alterations were observed for catalase activity, suggesting the absence of oxidative stress. On the contrary, significant alterations in glutathione-S-transferases activity were described for the higher concentrations of both pharmaceuticals after acute exposure. In addition, acute exposure to paracetamol caused a significant increase of cholinesterase activity. None of the tested pharmaceuticals caused significant changes in catalase or cholinesterase activities after chronic exposure. Glutathione S-transferases activity was significantly increased for propranolol following chronic exposure, indicating the potential involvement of phase II detoxification pathway.

Intravenous Acetaminophen Does Not Reduce Inpatient Opioid Prescription or Opioid-Related Adverse Events Among Patients Undergoing Spine Surgery.

BACKGROUND: Having entered the US market relatively recently, the perioperative role of intravenous acetaminophen (ivAPAP) remains to be established for several surgeries. Using national data, we therefore assessed current utilization and whether it reduces inpatient opioid prescription and opioid-related side effects in a procedure with relatively high opioid utilization. METHODS: Patients undergoing a lumbar/lumbosacral spinal fusion (n = 117,269; 2011-2014) were retrospectively identified in a nationwide database and categorized by the amount and timing of ivAPAP administration (1 or >1 dose on postoperative day [POD] 0, 1, or 1+). Multivariable models measured associations between ivAPAP utilization categories and opioid prescription and perioperative complications; odds ratios (or % change) and 95% confidence intervals are reported. RESULTS: Overall, ivAPAP was used in 18.9% (n = 22,208) of cases of which 1 dose on POD 0 was the most common (73.6%; n = 16,335). After covariate adjustment, use of ivAPAP on POD 0 and 1 was associated with minimal changes in opioid prescription, length and cost of hospitalization particularly favoring >1 ivAPAP dose with a modestly (-5.2%, confidence interval, -7.2% to -3.1%; P < .0001) decreased length of stay. Use of ivAPAP did not coincide with a consistent pattern of significantly reduced odds for complications. In comparison, the most commonly used nonopioid analgesic, pregabalin/gabapentin, did demonstrate reduced opioid prescription combined with lower complication risk. CONCLUSIONS: We could not show that perioperative ivAPAP reduces inpatient opioid prescription with subsequent reduced odds for adverse outcomes. It remains to be determined if and under what circumstances ivAPAP has a meaningful clinical role in everyday practice.

Concurrent assessment of calpain and caspase3 activities in brains of mice with acetaminophen-induced acute hepatic encephalopathy.

To develop pharmacological therapy for acute hepatic encephalopathy (AHE), understanding the molecular basis for cell injury is essential. Excitotoxic neural cell injury mediated by calpain as a post- receptor mechanism has been proposed as a player in neuronal injury in AHE. Concurrent assessment of Calpain and Caspase3 activities in the brain of AHE mice in acetaminophen- induced mourine model was performed. After induction of AHE by acetaminophen in mice, the model was confirmed by histopathological, biochemical and behavioural studies. The brains were removed, western blot analysis was done and the relative activity of calpain and caspase was estimated and compared to control group calpain but not caspase 3 activity was significantly increased in the AHE group compared to the control brains. Experimentally, this finding is the first to report. Increased calpain activity in liver has been previously reported. To translate both finding it can be suggested that calpain inhibition can be an investigational intervention in saving lives in AHE. To confirm the results, besides more advanced toxicodynamic studies on acetaminophen, the results should be confirmed in other models of AHE in future.

Evaluation of a Food and Drug Administration Mandate to Limit Acetaminophen in Prescription Combination Products.

INTRODUCTION: In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products. METHODS: Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome. RESULTS: A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as "major effect" and fewer cases being categorized as "no effect." CONCLUSIONS: The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N-acetylcysteine administration as reported to NPDS.

Estimating the impact of adopting the revised United Kingdom acetaminophen treatment nomogram in the U.S. population.

BACKGROUND: Acetaminophen toxicity is common in clinical practice. In recent years, several European countries have lowered the treatment threshold, which has resulted in increased number of patients being treated at a questionable clinical benefit. OBJECTIVE: The primary objective of this study is to estimate the cost and associated burden to the United States (U.S.) healthcare system, if such a change were adopted in the U.S. METHODS: This study is a retrospective review of all patients age 14 years or older who were admitted to one of eight different hospitals located throughout the U.S. with acetaminophen exposures during a five and a half year span, encompassing from 1 January 2008 to 30 June 2013. Those patients who would be treated with the revised nomogram, but not the current nomogram were included. The cost of such treatment was extrapolated to a national level. RESULTS: 139 subjects were identified who would be treated with the revised nomogram, but not the current nomogram. Extrapolating these numbers nationally, an additional 4507 (95%CI 3641-8751) Americans would be treated annually for acetaminophen toxicity. The cost of lowering the treatment threshold is estimated to be $45 million (95%CI 36,400,000-87,500,000) annually. CONCLUSIONS: Adopting the revised treatment threshold in the U.S. would result in a significant cost, yet provide an unclear clinical benefit.

Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management.

Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

Clinically significant hemodynamic alterations after propacetamol injection in the emergency department: prevalence and risk factors.

Propacetamol, a water-soluble prodrug form of paracetamol, is hydrolyzed by esterase to generate paracetamol in the blood. Each gram of propacetamol is equal to 0.5 g of paracetamol. It has been reported to cause hypotension in critically ill patients with a fever. We aimed to investigate the hemodynamic effects of propacetamol for the control of fever in patients with diverse severities of illness who were managed in the emergency department (ED). We also aimed to identify clinical factors related to significant hemodynamic alterations in ED patients. This was a retrospective study of 1507 ED patients who received propacetamol. Significant hemodynamic alterations were defined as systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP) <60 mmHg, or a drop in SBP >30 mmHg, which required treatments with a bolus of fluid or vasopressor administration. Postinfusion SBP and DBP were significantly lower than the preinfusion SBP and DBP. A clinically significant drop in BP occurred in 162 (10.7 %) patients, and interventions were necessary. Among the predictors assessed, congestive heart failure (OR 6.21, 95 % CI 2.67-14.45) and chills (OR 3.10, 95 % CI 2.04-4.70) were independent factors for a significant hemodynamic change. Administration of propacetamol can provoke a reduction in BP in ED patients. This reduction was clinically significant for 10 % of infusions. Clinicians should be aware of this potential deleterious effect, especially in patients with congestive heart failure or who experience chills prior to the administration of propacetamol.

The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study.

BACKGROUND: Toxic liver diseases are mainly caused by drug-induced liver injury (DILI). We assessed incidences and outcomes of DILI including associated factors for mortality. METHODS: We performed a population-based study of hospitalized patients with DILI. Information was retrieved from the Nationwide Hospital Admission Data using ICD-10 code of toxic liver diseases (K71) and additional codes (T36-T65). The associated factors were analyzed with log-rank test, univariate and multiple cox regression analysis. RESULTS: During 2009-2013, a total of 159,061 (average 21,165 per year) admissions were related to liver diseases. 6,516 admissions (1,303 per year) were due to toxic liver diseases. The most common type of toxic liver disease was acute hepatitis (33.5 %). In-hospital and 90-day mortality rates were 3.4 % and 17.2 %. DILI with cirrhosis yielded the highest in-hospital and 90-day mortality rates (15.8 % and 47.4 %). Acetaminophen, cirrhosis and age ≥ 60 years were seen in 0.5 %, 8.3 % and 50.1 % of patients who died versus 5 %, 2.3 % and 32.4 % of survivors. Factors associated with mortality were cirrhosis (HR 2.72, 95 % CI: 2.33-3.19), age ≥60 years (HR 2.16, 95 % CI: 1.96-2.38), human immunodeficiency viral infection (HR 2.11, 95 % CI: 1.88-2.36), chronic kidney disease (HR 1.59, 95 % CI: 1.33-1.90), chronic obstructive pulmonary disease and bronchiectasis (HR 1.55, 95 % CI: 1.17-2.04), malnutrition (HR 1.43, 95 % CI: 1.10-1.86) and male (HR 1.31, 95 % CI: 1.21-1.43). Acetaminophen DILI yielded lower risks of mortality (HR 0.24, 95 % CI: 0.13-0.42). The most common causes of DILI were acetaminophen (35.0 %) and anti-tuberculous drugs (34.7 %). CONCLUSIONS: DILI is an uncommon indication for hospitalization carrying lower risks of death except in patients with non-acetaminophen, cirrhosis, elderly or concomitant diseases.

The changing face of liver transplantation for acute liver failure: Assessment of current status and implications for future practice.

The etiology and outcomes of acute liver failure (ALF) have changed since the definition of this disease entity in the 1970s. In particular, the role of emergency liver transplantation has evolved over time, with the development of prognostic scoring systems to facilitate listing of appropriate patients, and a better understanding of transplant benefit in patients with ALF. This review examines the changing etiology of ALF, transplant benefit, outcomes following transplantation, and future alternatives to emergency liver transplantation in this devastating condition.