Evaluation of Health-Related Values and Preferences of Adults Who Were Preterm Infants and Parents of Preterm Infants Concerning Use of Prophylactic Cyclooxygenase Inhibitor Drugs.

Importance: There is wide variability in the use of prophylactic cyclooxygenase inhibitor (COX-I) drugs to prevent morbidity and mortality in preterm infants. Parents of preterm infants are rarely involved in this decision-making process. Objective: To explore the health-related values and preferences of adults who were preterm infants and families of preterm infants concerning the prophylactic use of indomethacin, ibuprofen, and acetaminophen initiated within the first 24 hours after birth. Design, Setting, and Participants: This cross-sectional study used direct choice experiments conducted in 2 phases of virtual video-conferenced interviews between March 3, 2021, and February 10, 2022: (1) a pilot feasibility study and (2) a formal study of values and preferences, using a predefined convenience sample. Participants included adults born very preterm (gestational age <32 weeks) or parents of very preterm infants currently in the neonatal intensive care unit (NICU) or having graduated from the NICU in the last 5 years. Main Outcomes and Measures: Relative importance of clinical outcomes, willingness to use each of the COX-Is when presented as the only option, preference for using prophylactic hydrocortisone vs indomethacin, willingness to use any of the COX-Is when all 3 options are available, and relative importance of having family values and preferences included in decision-making. Results: Of 44 participants enrolled, 40 were included in the formal study (31 parents and 9 adults born preterm). The median gestational age of the participant or the participant's child at birth was 26.0 (IQR, 25.0-28.8) weeks. Death (median score, 100 [IQR, 100-100]) and severe intraventricular hemorrhage (IVH) (median score, 90.0 [IQR, 80.0-100]) were rated as the 2 most critical outcomes. Based on direct choice experiments, most participants were willing to consider prophylactic indomethacin (36 [90.0%]) or ibuprofen (34 [85.0%]), but not acetaminophen (4 [10.0%]) when offered as the only option. Among participants who initially chose indomethacin (n = 36), if prophylactic hydrocortisone was offered as a potential therapy with the caveat that both cannot be used simultaneously, only 12 of 36 (33.3%) preferred to remain with indomethacin. Variability in preference was noted when all 3 COX-I options were available, indomethacin (19 [47.5%]) being the most preferred option followed by ibuprofen (16 [40.0%]), while the remainder opted for no prophylaxis (5 [12.5%]). Conclusions and Relevance: The findings of this cross-sectional study of former preterm infants and parents of preterm infants suggest that there was minimal variability in how participants valued the main outcomes, with death and severe IVH being rated as the 2 most important undesirable outcomes. While indomethacin was the most preferred form of prophylaxis, variability was noted in the choice of COX-I interventions when participants were presented with the benefits and harms of each drug.

The effect of metformin and drinking water quality variation on haloacetamide formation during chlor(am)ination of acetaminophen.

Acetaminophen (Apap) is widely used and is known to form toxic haloacetamides (HAcAms) during chlorination. Metformin (Met) is a typical medication with usage much higher than that of Apap and its ubiquitous presence in the environment is known. The objective of this study was to investigate the effects of Met which contains multiple amino groups potentially joining reactions and different chlorination methods on HAcAm formation from Apap. In addition, a major drinking water treatment plant (DWTP) using the largest river in southern Taiwan was sampled to study the influence of Apap in a DWTP on the HAcAm formation. Results showed increasing dichloroacetamide (DCAcAm) molar yields of Apap at a Cl/Apap molar ratio of 5 during chlorination (0.15%) and two-step chlorination (0.03%). HAcAms were formed by the chlorine substitution of hydrogen on the methyl group in Apap followed by the cleavage of the bonding between nitrogen and aromatic. While a high Cl/Apap ratio during chlorination led to reactions between chlorine and HAcAms formed decreasing the HAcAm yields, the two-step chlorination further reduced the HAcAm formation during chlorination by a factor of 1.8-8.2. However, Met which limitedly formed HAcAms increased the DCAcAm yields of Apap by 228% at high chlorine dosages during chlorination and by 244% during two-step chlorination. In the DWTP, trichloroacetamide (TCAcAm) formation was important. The formation was positively correlated with NH4+, dissolved organic carbon (DOC), and specific ultraviolet absorbance (SUVA). DCAcAm dominated in the presence of Apap. The DCAcAm molar yields were 0.17%-0.27% and 0.08%-0.21% in the wet and dry seasons, respectively. The HAcAm yields of Apap in the DWTP were limitedly changed between different locations and seasons. Apap could be one important cause for HAcAm formation in a DWTP, as the presence of other pharmaceuticals such as Met possibly worsens the situation in chlorine applications.

The role of Human Development Index in the epidemiology of asthma in adolescents in Kosovo: A cross-sectional multicentre Global Asthma Network (GAN) study.

BACKGROUND: Very limited information is available on the prevalence and risk factors of asthma in adolescents in Kosovo, and no study has previously addressed the role of Human Development Index (HDI) on asthma in the region. The present study addresses these two issues. METHODS: Following the Global Asthma Network (GAN) methodology, a cross-sectional survey, through standardised self-completed questionnaires, was conducted in the following six centres of Kosovo: Ferizaj, Gjakova, Gjilan, Peja, Prishtina and Prizren. Current asthma symptoms (CAS) and severe current asthma symptoms (sCAS) were defined according to the GAN standards. Environmental questionnaire inquired about gender, exercise, screening time, siblings, truck traffic, use of paracetamol, pet ownership, and smoking habits. Height and weight were also measured. Multivariate logistic regression analyses were performed in each centre along with meta-analyses to summarise the overall effects of each factor in the centres as a whole. Meta-regression of the prevalence rates was calculated using HDI as a moderator. RESULTS: Participation rate was high (80.0-99.9%). Prevalence of CAS ranged from 4.6% to 11.3%, and sCAS from 1.7% to 4.5%. Factors associated with CAS were exercise, computer time, paracetamol use and dog ownership. sCAS was associated with paracetamol use and physical exercise. HDI explained 46% and 80% of prevalence variability of CAS and sCAS between centres, respectively. CONCLUSIONS: Prevalence of CAS and sCAS in Kosovo varies highly between centres. This variability is explained partly by HDI. Individual risk factors are common, with some determined in other studies conducted in other regions.

Evaluation of the Defined Bacterial Consortium Efficacy in the Biodegradation of NSAIDs.

Due to the increasing pollution of wastewater with non-steroidal anti-inflammatory drugs, preparations need to be developed to decompose these drugs. This work aimed to develop a bacterial consortium with a defined composition and boundary conditions for the degradation of paracetamol and selected non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, and diclofenac. The defined bacterial consortium consisted of Bacillus thuringiensis B1(2015b) and Pseudomonas moorei KB4 strains in a ratio of 1:2. During the tests, it was shown that the bacterial consortium worked in the pH range from 5.5 to 9 and temperatures of 15-35 °C, and its great advantage was its resistance to toxic compounds present in sewage, such as organic solvents, phenols, and metal ions. The degradation tests showed that, in the presence of the defined bacterial consortium in the sequencing batch reactor (SBR), drug degradation occurred at rates of 4.88, 10, 0.1, and 0.05 mg/day for ibuprofen, paracetamol, naproxen, and diclofenac, respectively. In addition, the presence of the tested strains was demonstrated during the experiment as well as after its completion. Therefore, the advantage of the described bacterial consortium is its resistance to the antagonistic effects of the activated sludge microbiome, which will enable it to be tested in real activated sludge conditions.

Association of OPRM1, MIR23B, and MIR107 genetic variability with acute pain, chronic pain and adverse effects after postoperative tramadol and paracetamol treatment in breast cancer.

BACKGROUND: Tramadol is an opioid analgesic often used for pain management after breast cancer surgery. Its analgesic activity is due to the activation of the µ-opioid receptor, encoded by the OPRM1 gene. This study investigated the association of genetic variability in OPRM1 and its regulatory miRNA genes with outcomes of tramadol/paracetamol treatment after breast cancer surgery with axillary lymphadenectomy. PATIENTS AND METHODS: The study included 113 breast cancer patients after breast cancer surgery with axillary lymphadenectomy treated with either 75/650 mg or 37.5/325 mg of tramadol with paracetamol for pain relief within the randomized clinical trial KCT 04/2015-DORETAonko/si at the Institute of Oncology Ljubljana. All patients were genotyped for OPRM1 rs1799971 and rs677830, MIR23B rs1011784, and MIR107 rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain as well as adverse effects of tramadol treatment was evaluated using logistic regression, Fisher's exact test, and Mann-Whitney test. RESULTS: The investigated OPRM1 related polymorphisms were not associated with acute pain assessed with the VAS scale within four weeks after surgery (all P > 0.05). Carriers of at least one polymorphic OPRM1 rs1799971 allele had a higher risk of constipation in the first four weeks after surgery compared to non-carriers (OR = 4.5, 95% CI = 1.6-12.64, P = 0.004). Carriers of at least one polymorphic OPRM1 rs677830 allele had a higher risk of constipation after third week of tramadol treatment (OR = 3.11, 95% CI = 1.08-8.89, P = 0.035). Furthermore, carriers of two polymorphic MIR23B rs1011784 alleles had a higher risk of nausea after 28 days of tramadol treatment (OR = 7.35, 95% CI = 1.27-42.6, P = 0.026), while heterozygotes for MIR107 rs2296616 allele had a lower risk of nausea after 21 days of tramadol treatment (OR = 0.21, 95% CI = 0.05-0.87, P = 0.031). In carriers of two polymorphic MIR107 rs2296616 alleles, chronic pain was significantly more common than in carriers of two wild-type alleles (P = 0.004). Carriers of at least one polymorphic MIR23B rs1011784 allele experienced more neuropathic pain after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036), while carriers of at least one polymorphic OPRM1 rs677830 allele experienced less neuropathic pain compared to carriers of two wild-type alleles (OR = 0.38, 95% CI = 0.15-0.99, P = 0.047). CONCLUSIONS: Genetic variability of OPRM1 and genes coding for miRNAs that could affect OPRM1 expression may be associated with adverse effects of tramadol/paracetamol treatment as well as with chronic and neuropathic pain after breast cancer surgery with axillary lymphadenectomy.

Molecular mechanism of the protective effect of adenosine triphosphate against paracetamol-induced liver toxicity in rats.

Toxic doses of paracetamol are also known to be close to therapeutic doses. This study aimed to biochemically investigate the protective effect of ATP against paracetamol-induced oxidative liver injury in rats and to examine the tissues histopathologically. We divided the animals into the paracetamol alone (PCT), ATP + paracetamol (PATP), and healthy control (HG) groups. Liver tissues were examined biochemically and histopathologically. Malondialdehyde level, AST and ALT activity in the PCT group were significantly higher than those in the HG and PATP groups (p < 0.001). The glutathione (tGSH) level, superoxide dismutase (SOD) and catalase (CAT) activity in the PCT group was significantly lower than that in the HG and PATP groups (p < 0.001), while animal SOD activity was significantly different between the PATP and HG groups (p < 0.001). The activity of CAT was almost the same. In the group treated with paracetamol alone, lipid deposition, necrosis, fibrosis, and grade 3 hydropic degeneration were observed. No histopathological damage was observed of the ATP-treated group, except for grade 2 edema. We discovered that ATP reduces the oxidative stress caused by paracetamol ingestion and protects against paracetamol-induced liver injury at the macroscopic and histological levels.

Serious Clinical Outcomes of COVID-19 Related to Acetaminophen or NSAIDs from a Nationwide Population-Based Cohort Study.

Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed to infected patients; however, the safety of them has not been investigated in patients with serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to evaluate the association between the previous use of acetaminophen or NSAIDs and the clinical outcomes of SARS-CoV-2 infection. A nationwide population-based cohort study was conducted using the Korean Health Insurance Review and Assessment Database through propensity score matching (PSM). A total of 25,739 patients aged 20 years and older who tested for SARS-CoV-2 were included from 1 January 2015 to 15 May 2020. The primary endpoint was a positive result for a SARS-CoV-2 test, and the secondary endpoint was serious clinical outcomes of SARS-CoV-2 infection, such as conventional oxygen therapy, admission to the intensive care unit, need for invasive ventilation care, or death. Of 1058 patients, after propensity score matching, 176 acetaminophen users and 162 NSAIDs users were diagnosed with coronavirus disease 2019. After PSM, 162 paired data sets were generated, and the clinical outcomes of the acetaminophen group were not significantly different from those of the NSAIDs group. This suggests that acetaminophen and NSAIDs can be used safely to control symptoms in patients suspected of having SARS-CoV-2.

[Discovery of miRNA and target signal molecules involved in inhibition of chlorogenic acid on N-acetyl-p-aminophenol-induced hepatotoxicity based on microRNA array].

This study aims to observe the effect of chlorogenic acid(CGA) on microRNA(miRNA) in the process of protecting against N-acetyl-p-aminophenol(APAP)-induced liver injury. Eighteen C57BL/6 mice were randomly assigned into a normal group, a model group(APAP, 300 mg·kg~(-1)), and a CGA(40 mg·kg~(-1)) group. Hepatotoxicity of mice was induced by intragastric administration of APAP(300 mg·kg~(-1)). The mice in the CGA group were administrated with CGA(40 mg·kg~(-1)) by gavage 1 h after APAP administration. The mice were sacrificed 6 h after APAP administration, and plasma and liver tissue samples were collected for the determination of serum alanine/aspartate aminotransferase(ALT/AST) level and observation of liver histopathology, respectively. MiRNA array combined with real-time PCR was employed to discover important miRNAs. The target genes of miRNAs were predicted via miRWalk and TargetScan 7.2, verified by real-time PCR, and then subjected to functional annotation and signaling pathway enrichment. The results showed that CGA administration lowered the serum ALT/AST level elevated by APAP and alleviate the liver injury. Nine potential miRNAs were screened out from the microarray. The expression of miR-2137 and miR-451a in the liver tissue was verified by real-time PCR. The expression of miR-2137 and miR-451a was significantly up-regulated after APAP administration, and such up-regulated expression was significantly down-regulated after CGA administration, consistent with the array results. The target genes of miR-2137 and miR-451a were predicted and verified. Eleven target genes were involved in the process of CGA protecting against APAP-induced liver injury. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment with DAVID and R language showed that the 11 target genes were enriched in Rho protein-related signal transduction, vascular patterning-related biological processes, binding to transcription factors, and Rho guanyl-nucleotide exchange factor activity. The results indicated that miR-2137 and miR-451a played an important role in the inhibition of CGA on APAP-induced hepatotoxicity.

Mass flow and consumption calculations of pharmaceuticals in sewage treatment plant with emphasis on the fate and risk quotient assessment.

In Egypt, pharmaceuticals consumption increased dramatically owing to the population growth and the unrestricted sale manner. Accordingly, the occurrence and fate of nine common pharmaceutical active compounds (PhACs) were scrutinized at a sewage treatment plant (STP) in Giza, Egypt. The levels of these PhACs were assessed in different the wastewater treatment stages and dewatered sludge phase using high-performance liquid chromatography coupled with photodiode arrays detector. The average concentrations of the total PhACs detected in influent, primary sedimentation effluent (PSE) and final effluent (FE) were 227, 155 and 89 µg L-1, respectively. The overall removal efficiency of the individual PhACs ranged from 18 to 72% removal. The occurrence trend revealed that biodegradation and adsorption are the concurrently removal mechanisms of the studied PhACs. The overall consumption per day in West of Greater Cairo was estimated based on influent concentration of STP. Sulfamethoxazole, paracetamol and diclofenac were detected with the highest levels in the influent of STP, PSE and FE as well as in the dewatered sludge. Furthermore, the high concentrations of these compounds in the sludge confirm the adsorption pathway removal of theses PhACs. The risk quotient (RQ) assessment for the detected PhACs in FE is greatly higher than the predicted non-effect concentration (PNEC). Conclusively, the FE of STP is considered a risky source for PhACs in adjacent surface water.

Paracetamol and ibuprofen combination for the management of acute mild-to-moderate pain in children: expert consensus using the Nominal Group Technique (NGT).

BACKGROUND: Acute pain is a common symptom in children of all ages, and is associated with a variety of conditions. Despite the availability of guidelines, pain often remains underestimated and undertreated. Paracetamol and ibuprofen are the most commonly used drugs for analgesia in Pediatrics. Multimodal pain management by using a combination of paracetamol and ibuprofen results in greater analgesia. METHODS: An investigation using the Nominal Group Technique was carried out between May and August 2022. Two open (non-anonymous) questionnaires were consecutively sent to a Board of ten clinicians to understand their opinions on the use of the oral paracetamol and ibuprofen association. Answers were examined in a final meeting where conclusions were drawn. RESULTS: The board achieved a final consensus on a better analgesic power of paracetamol and ibuprofen in fixed-dose combination as compared to monotherapy, without compromising safety. Strong consensus was reached on the opinion that the fixed-dose combination of paracetamol and ibuprofen may be a useful option in case of inefficacy of one or other drug as monotherapy, especially in case of headaches, odontalgia, earache, and musculoskeletal pain. The use of the fixed combination may be also considered suitable for postoperative pain management. CONCLUSIONS: The use of the fixed-dose combination may represent advantage in terms of efficacy and safety, allowing a better control of the dose of both paracetamol and ibuprofen as monotherapy, thus minimizing the risk of incorrect dosage. However, the limited evidence available highlights the need for future well designed studies to better define the advantages of this formulation in the various therapeutic areas.

Systemic opioids versus other analgesics and sedatives for postoperative pain in neonates.

BACKGROUND: Neonates may undergo surgery because of malformations such as diaphragmatic hernia, gastroschisis, congenital heart disease, and hypertrophic pyloric stenosis, or complications of prematurity, such as necrotizing enterocolitis, spontaneous intestinal perforation, and retinopathy of prematurity that require surgical treatment. Options for treatment of postoperative pain include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. The assessment of the effects of opioids is of utmost importance, especially for neonates in substantial pain during the postoperative period. OBJECTIVES: To evaluate the benefits and harms of systemic opioid analgesics in neonates who underwent surgery on all-cause mortality, pain, and significant neurodevelopmental disability compared to no intervention, placebo, non-pharmacological interventions, different types of opioids, or other drugs. SEARCH METHODS: We searched Cochrane CENTRAL, MEDLINE via PubMed and CINAHL in May 2021. We searched the WHO ICTRP, clinicaltrials.gov, and ICTRP trial registries. We searched conference proceedings, and the reference lists of retrieved articles for RCTs and quasi-RCTs.  SELECTION CRITERIA: We included randomized controlled trials (RCTs) conducted in preterm and term infants of a postmenstrual age up to 46 weeks and 0 days with postoperative pain where systemic opioids were compared to 1) placebo or no intervention; 2) non-pharmacological interventions; 3) different types of opioids; or 4) other drugs.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods, all-cause mortality during initial hospitalization, major neurodevelopmental disability, and cognitive and educational outcomes in children more than five years old. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four RCTs enrolling 331 infants in four countries across different continents. Most studies considered patients undergoing large or medium surgical procedures (including major thoracic or abdominal surgery), who potentially required pain control through opioid administration after surgery. The randomized trials did not consider patients undergoing minor surgery (including inguinal hernia repair) and those individuals exposed to opioids before the beginning of the trial. Two RCTs compared opioids with placebo; one fentanyl with tramadol; and one morphine with paracetamol. No meta-analyses could be performed because the included RCTs reported no more than three outcomes within the prespecified comparisons. Certainty of the evidence was very low for all outcomes due to imprecision of the estimates (downgrade by two levels) and study limitations (downgrade by one level).  Comparison 1: opioids versus no treatment or placebo Two trials were included in this comparison, comparing either tramadol or tapentadol with placebo. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of tramadol compared with placebo on all-cause mortality during initial hospitalization (RR 0.32, 95% Confidence Interval (CI) 0.01 to 7.70; RD -0.03, 95% CI -0.10 to 0.05, 71 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.  Comparison 2: opioids versus non-pharmacological interventions No trials were included in this comparison. Comparison 3: head-to-head comparisons of different opioids One trial comparing fentanyl with tramadol was included in this comparison. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of fentanyl compared with tramadol on all-cause mortality during initial hospitalization (RR 0.99, 95% CI 0.59 to 1.64; RD 0.00, 95% CI -0.13 to 0.13, 171 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.  Comparison 4: opioids versus other analgesics and sedatives One trial comparing morphine with paracetamol was included in this comparison. The evidence is very uncertain about the effect of morphine compared with paracetamol on COMFORT pain scores (MD 0.10, 95% CI -0.85 to 1.05; 71 participants, 1 study; I² = not applicable).  No data were reported on the other critical outcomes, i.e. major neurodevelopmental disability; cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization; retinopathy of prematurity; or intraventricular hemorrhage. AUTHORS' CONCLUSIONS: Limited evidence is available on opioid administration for postoperative pain in newborn infants compared to either placebo, other opioids, or paracetamol. We are uncertain whether tramadol reduces mortality compared to placebo; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether fentanyl reduces mortality compared to tramadol; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether morphine reduces pain compared to paracetamol; none of the studies reported major neurodevelopmental disability, cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization, retinopathy of prematurity, or intraventricular hemorrhage. We identified no studies comparing opioids versus non-pharmacological interventions.

Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.

Importance: In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014. Objective: To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate. Design, Setting, and Participants: This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG. Exposures: Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products. Main Outcomes and Measures: Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate. Results: In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings. Conclusions and Relevance: The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.

Most common over-the-counter medications and effects on patients.

OBJECTIVE: The self-medicating practice of using over-the-counter (OTC) medications are more common than prescription drug use worldwide. OTC drugs are primarily used to treat conditions that do not require direct medical attention or supervision, and OTC drugs must be demonstrated to be reasonably safe and well-tolerated. The pharmacy profession describes their role in dispensing over-the-counter (OTC) products as "selecting the best medication according to reported symptoms". This study aimed to evaluate the use of most common over-the-counter (OTC) medications and their effect on patients. PATIENTS AND METHODS: A cross-sectional survey-based study was conducted on 442 participants who used OTC drugs from June to November 2021. RESULTS: The most common OTC drugs used by patients involved in the study were paracetamol (13.35%), followed by ibuprofen (2.04%). Gender of patients was significantly related to (duration, frequency, suggestion, and misuse) of OTC use and patient counseling by the pharmacist (p<0.05). CONCLUSIONS: OTC medications can easily be obtained at pharmacies for the purpose of self-treatment. The most common OTC drugs used by the studied patients were paracetamol, followed by ibuprofen. It is suggested that an awareness program among community people be conducted at the community level regarding over-the-counter (OTC) drugs.

Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina.

Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a ß-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [-]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [-] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [-] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.

Highly Efficient Electrochemical Sensing of Acetaminophen by Cobalt Oxide-Embedded Nitrogen-Doped Hollow Carbon Spheres.

With respect to sensor application investigations, hollow mesoporous carbon sphere-based materials of the spinel type of cobalt oxide (Co3O4) and heteroatom-doped materials are gaining popularity. In this contribution, dopamine hydrochloride (DA) and cobalt phthalocyanine (CoPc) precursors were employed to construct a highly homogeneous Co3O4-embedded N-doped hollow carbon sphere (Co3O4@NHCS) by a straightforward one-step polymerization procedure. The resulting Co3O4@NHCS materials may effectively tune the surface area, defect sites, and doping amount of N and Co elements by altering the loading amount of CoPc. The relatively high surface area, greater spherical wall thickness, enriched defect sites, and better extent of N and Co sites are all visible in the best 200 mg loaded Co3O4@NHCS-2 material. This leads to significant improvement in pyridine and graphitic N site concentrations, which offers exceptional electrochemical performance. Electrochemical analysis was used to study the electrocatalytic activity of Co3O4@NHCSs towards the sensing of pharmacologically active significant compounds (acetaminophen). Excellent sensor properties include the linear range (0.001-0.2 and 1.0-8.0 mM), sensitivity, limit of detection (0.07 and 0.11 µM), and selectivity in the modified Co3O4@NHCSs/GCE. The authentic sample (acetaminophen tablet) produces a satisfactory result when used practically.

A Multimodal Protocol to Limit Opioid Exposure and Effectively Manage Postoperative Cesarean Birth Pain.

PURPOSE: To evaluate the impact of implementing a multimodal plan of care in treating the pain of the postoperative cesarean birth patient that limited opioid exposure. STUDY DESIGN AND METHODS: A retrospective medical record review was conducted to evaluate a pain management protocol implemented for postoperative cesarean patients before and after a practice change. Sample included term postoperative cesarean patients ≥ 37 weeks of gestation, who had spinal or epidural, were 18 years or older, gave birth to a singleton newborn, admitted to the maternal child health department, and were prescribed opioids as a postoperative pain management treatment plan. Participants (N = 150) were evaluated based on two groups: n = 75 in the preimplementation group and n = 75 in the postimplementation group. RESULTS: There was a significant difference in the total oral opioid milligrams administered between the pregroup (M = 27.13) and postgroup (M = 8.43), after the practice change (p < .001). There was an increase of nonopioids administered to treat and manage postoperative cesarean pain, Motrin PO (p = < .001) and Tylenol PO (p = .002). CLINICAL IMPLICATIONS: Fewer milligram equivalents of morphine were administered when postoperative cesarean patients were placed on scheduled nonopioids to treat pain.

Rational design and appraisal of selective Cdc2-Like kinase 1 (Clk1) inhibitors as novel autophagy inducers for the treatment of acute liver injury (ALI).

Autophagy inducers are promising agents for treating certain medical illnesses, while no safe autophagy inducers are in clinical applications. Cdc2-like kinase 1 (Clk1) inhibitors induce autophagy efficiently; however, most Clk1 inhibitors lack selectivity, especially against Dyrk1A kinase. Herein, we report a series of 1H-pyrrolo[2,3-b]pyridin-5-amine derivatives as novel Clk1 inhibitors. Through detailed structural modification and structure-activity relationship studies, compound 10ad shows potent and selective inhibition for Clk1, with an IC50 value of 5 nM and over 300-fold selectivity for Dyrk1A. Related kinase screening also validates the selectivity of compound 10ad. Furthermore, compound 10ad potently induces autophagy in vitro and exhibits significant hepatoprotective effects in the acute liver injury model induced by acetaminophen (paracetamol). In general, due to the excellent potency and selectivity, compound 10ad was worth further investigation in the treatment of autophagy-related diseases.

Piezo1 alleviates acetaminophen-induced acute liver injury by activating Nrf2 and reducing mitochondrial reactive oxygen species.

Acetaminophen (APAP) overdose is the most common cause for acute liver failure (ALF) in the developed countries, with limited treatment options. Piezo1 is a mechanosensitive cation channel. We found that APAP caused upregulation of Piezo1 in both an APAP-induced acute liver injury (ALI) animal model and a mouse hepatocyte cell line AML12. Activation of Piezo1 by its activator Yoda1 reduced APAP-induced hepatotoxicity and ROS level. Mechanistically, activation of Piezo1 led to accumulation of the antioxidant regulator Nrf2 and upregulation of its target genes Nqo1 and Gsta1, while knockdown of Piezo1 downregulated this pathway. Finally, injection of Yoda1 decreased serum AST and ALT levels, reduced cell death and rescued liver injury in the APAP-induced ALI mouse model. Our findings suggested a previously undiscovered protective role of Piezo1 in APAP-induced ALI, which might shed light on a new therapeutic target for this disease.