Dose Of Acetaminophen Research Articles

6898 A Case Report Of Drug-Induced Liver Injury Secondary To Sublingual Estradiol In A Transgender Woman

Abstract Disclosure: F. Manas: None. E. Davydov: None. A. Caines: None. K. Estrada: None. J.E. Shill: None. Drug-induced liver injury (DILI), the leading cause of acute liver failure in the United States, occurs in response to a medication or natural compound. Estrogens can lead to idiosyncratic DILI. According to LiverTox [livertox.nih.gov], estrogen has a likelihood score of A (highly likely) to cause DILI, whereas spironolactone has a likelihood score of D (rare). The current formulations of estrogens usually produce a mixed or cholestatic pattern of liver enzyme elevations, however very early, the ALT levels can be markedly elevated (5- to 20-fold). One can be asymptomatic. Often the liver injury resolves after removing the offending agent. We present a case of DILI with elevations of both alanine transferase (ALT) and aspartate transferase (AST), secondary to sublingual estradiol (E2). A 23-year-old transgender female presented for feminizing gender-affirming care. She was started on sublingual E2 2 mg once daily and spironolactone 100 mg orally twice daily. Approximately 14 weeks later, sublingual E2 was increased to 2 mg twice daily for a below-target E2 level, and spironolactone was decreased to 50 mg twice daily due to gas and nausea. Routine blood work three weeks later showed elevated liver function tests (LFTs) in a hepatocellular pattern with ALT of 216 IU/L (normal:<52IU/L), AST of 223 IU/L (normal:<35 IU/L), with normal total bilirubin and alkaline phosphatase. LFTs were normal six months prior. At the time of liver injury, she had consumed six alcoholic beverages in the previous fourteen days, and two doses of acetaminophen. She had no personal history of autoimmunity and no family history of liver disease. Acute hepatitis screen was normal. Abdominal US with liver Doppler was unremarkable. E2 and spironolactone were discontinued. Evaluation by hepatology lead to a diagnosis of DILI from sublingual E2, based on the temporal relationship between initiation of E2 and LFT elevation. Other potential causes of elevated LFTs were excluded. Although she reported alcohol use, the AST/ALT elevation was not in a classic 2:1 pattern. Three weeks after cessation of E2 and spironolactone, her LFTs normalized. Spironolactone was resumed along with E2 by patch, but due to skin-adherence issues she was transitioned to injectable E2 valerate. Her LFTs have remained normal since. This case illustrates a rare but potentially dangerous adverse event of DILI secondary to sublingual E2. Due to the low incidence of liver injury in various studies of individuals with gender incongruence on hormone therapy, current evidence does not support routine liver enzyme monitoring. Clinicians should be aware of the potential risk of liver injury and counsel patients accordingly. As in this case, patients may be successfully rechallenged with the offending DILI medication. Further studies on different formulations of hormone therapy and their effects on the liver would be beneficial in this unique population. Presentation: 6/2/2024

The Ocular Penetration and Intraocular Pressure Lowering Effect of Topical Acetaminophen in the New Zealand White Rabbit.

Purpose: Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [N-arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR). Methods: A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs. Results: The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18-5.00) at 2 h and 0.92 ppm (0.60-1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was -5.1 mmHg⋅h (95% CI: -10 to 0.41) for control,-7.5 mmHg⋅h (95% CI: -14 to -1.1) for half-hourly acetaminophen, and -4.4 mmHg⋅h (95% CI: -14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was -2.3 mmHg⋅h (95% CI: -5.9 to 1.3) for control,-2.0 mmHg⋅h (95% CI: -5.6 to 1.7) for AM404, -1.7 mmHg⋅h (95% CI: -4.5 to 1.2) for acetaminophen, and -3.2 mmHg⋅h (95% CI: -5.4 to -0.96) for acetaminophen/AM404 combined. Conclusions: Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.

Acetaminophen effects upon formalin-evoked flinching, postformalin, and postincisional allodynia and conditioned place preference.

We explored in mice, the analgesic, tolerance, dependency, and rewarding effects of systemic acetaminophen (APAP). Studies employed adult mice (C57Bl6). (1) Intraplantar formalin flinching + post formalin allodynia. Mice were given intraperitoneal APAP in a DMSO (5%)/Tween 80 (5%) or a water-based formulation before formalin flinching on day 1 and tactile thresholds assessed before and after APAP at day 12. (2) Paw incision. At 24 hours and 8 days after hind paw incision in male mice, effects of intraperitoneal APAP on tactile allodynia were assessed. (3) Repeated delivery. Mice received daily (4 days) analgesic doses of APAP or vehicle and tested upon formalin flinching on day 5. (4) Conditioned place preference. For 3 consecutive days, vehicle was given in the morning in either of 2 chambers and in each afternoon, an analgesic dose of morphine or APAP in the other chamber. On days 5 and 10, animals were allowed to select a "preferred" chamber. Formalin in male mice resulted in biphasic flinching and an enduring postformalin tactile allodynia. Acetaminophen dose dependently decreased phase 2 flinching, and reversed allodynia was observed postflinching. At a comparable APAP dose, female mice showed similarly reduced phase 2 flinching. Incision allodynia was transiently reversed by APAP. Repeated APAP delivery showed no loss of effect after sequential injections or signs of withdrawal. Morphine, but not APAP or vehicle, resulted in robust place preference. APAP decreased flinching and allodynia observed following formalin and paw incision and an absence of tolerance, dependence, or rewarding properties.

Experimental model of systemic inflammation during acetaminophen toxicity

Acetaminophen is one of the most toxic drugs that can cause liver damage. At the same time, acetaminophen-induced liver failure is closely associated with the development of systemic inflammatory response syndrome. However, there is no drug aimed at suppressing the systemic inflammatory response. That is, this issue needs to be studied experimentally, but a model of systemic inflammation during acetaminophen overdose has not yet been obtained. Therefore, it was decided to develop an experimental model of systemic inflammation during acetaminophen overdose. The purpose of this study was to experimentally substantiate the semi-lethal dose for acetaminophen overdose in C57Bl/6 mice and to evaluate the readings of blood tests after administration of the drug. To determine the semi-lethal dose, male C57Bl/6 mice were intraperitoneally injected with “Ifimol” (Unique Pharmaceutical Laboratories, India) or acetaminophen solution (Sigma-Aldrich, USA) with a concentration of 14 mg/ml in different doses. When introducing “Ifimol”, it was not possible to achieve a semi-lethal dose. When administering a solution of acetaminophen, 50% mortality was recorded at a dose of 600 mg/kg body weight. After establishing a semi-lethal dose, the experimental group was administered an acetaminophen solution (Sigma-Aldrich, USA) with a concentration of 14 mg/ml at a dose of 600 mg/kg. The control group was injected with saline in an equivalent volume. On the second day, liver and peripheral blood samples were taken. Subsequently, hematological and biochemical blood tests and histological analysis were performed. Histological examination revealed centrilobular necrosis and disorganization of the liver structure. According to the biochemical blood test, the activity of aspartate aminotransferase, alanine aminotransferase, creatinine concentration, and the de Ritis coefficient differed statistically significantly (p 0.05) in the experimental group compared to the control group. Among the hematological blood test parameters, there were statistically significant differences in the number of leukocytes, platelets, as well as the absolute and relative content of granulocytes and lymphocytes. Thus, 48 hours after administration of a semi-lethal dose of acetaminophen, there were signs of damage to internal organs (liver, kidneys) and changes in immune system parameters, which are similar to components of systemic inflammation in humans.

Comparison of ropivacaine with ropivacaine–dexamethasone combination for postoperative analgesia in the pectoral nerve block for modified radical mastectomy: A randomized clinical trial

Abstract Background and Aims: The pectoral nerve block types I and II are novel techniques to provide analgesia for modified radical mastectomy (MRM) surgeries performed under general anesthesia. The primary objective of this study was to compare the duration of effective analgesia, and the secondary objectives were to evaluate the total amount of rescue analgesics in 24 h, hemodynamic changes, and postoperative adverse effects. Methods: This prospective, randomized, double-blind study was conducted on a total of 80 women with breast cancer belonging to American Society of Anesthesiologist class I and II scheduled for MRM, which were randomly allocated into two groups – Group R (n = 40) received 0.25% ropivacaine 29 ml + NS 1 ml and Group RD (n = 40) received 0.25% ropivacaine 29 ml + dexamethasone (4 mg) 1 ml. Ten milliliters of the study drug was used in Pecs I and the rest 20 ml in Pecs II block posttumor resection. Results: The duration of analgesia was statistically significantly longer in RD (778.75 ± 55.12 min) compared to Group R (412.63 ± 21.69 min) (P < 0.05). Pain scores were significantly less in Group RD. The mean dose of acetaminophen required was significantly less in Group RD (2362.50 ± 375.32 mg) than in Group R (3525.00 ± 298.50 mg) (P < 0.05). The incidence of adverse events was similar in both groups. Conclusion: The addition of dexamethasone with ropivacaine in the Pecs block can be used for prolonging the effective duration of analgesia and decreasing postoperative analgesic consumption with comparable hemodynamic and side effect profiles.

Impact of Neuraxial Preservative-Free Morphine in Vaginal Delivery on Opiate Consumption and Recovery: A Randomized Control Trial.

Neuraxial opioids are commonly used after cesarean delivery (CD). However, they are not commonly used after vaginal delivery (VD) though some studies have suggested they may be beneficial from a pain perspective. However, they did not evaluate other potential benefits including patient satisfaction, impact on postpartum depression and breastfeeding (BF) success, or side effects such as pruritus. Parturients who delivered vaginally with epidural analgesia were randomized to receive either 2 mg of preservative-free morphine (4 mL) or saline (4 mL) via the epidural catheter within 1 hour of VD. Routine analgesics were unchanged and included q 6-hour dosing of acetaminophen 975 mg orally and ketorolac 30 mg intravenous (IV). Hydromorphone 2 mg or oxycodone 10 mg were offered for breakthrough pain. Our primary outcome was opiate consumption in the first 24 hours after drug administration. Secondary outcomes included pain scores at 24 hours and 1 week postpartum as well as opiate consumption up to 1 week postpartum. Additional end points such as obstetric quality of recovery score (OBS-QOR10) breast feeding success, and an Edinburgh Postnatal Depression Score (EPDS) were also obtained. Data were analyzed for 157 parturients, 80 in the morphine group and 77 in the saline group. No difference was observed in the EDPS score predelivery or intention to BF. We found a statistically significant difference in the use of opioids in the first 24 hours, 3.8% (95% confidence interval [CI], 0.9%-11.3%) vs 14.3% (7.7%-24.5%) in the morphine and saline groups, respectively; and in total opioid dose, median (interquartile range, IQR [range]) of morphine milligram equivalent vs 0 (0-0 [0-47.5]) vs 0 (0-0 [0-72]), P = .023, in the morphine and saline groups, respectively. Verbal pain scores (0-10) at 24 hours were lower in the morphine group (median (IQR [range): 2.0 (1-4 [0-10]) vs 3.0 (1.5-5.0 [0-10]), P = .043. There was a greater incidence of pruritus in the morphine group versus saline group, 37.5% (95% CI, 27.1%-49.1%) vs 18.2% (95% CI, 10.6%-29.0%), P = .008. We did not find any differences in the OBS-QOR10, BF success, or EPDS at 6 weeks PP (P < .05). A single epidural dose of 2 mg preservative-free morphine after VD was effective at decreasing pain and opioid use at 24 hours after VD but came at the cost of increased pruritus. We did not detect any differences in BF, recovery scores, or PPD. Future studies should focus on elucidating the role of neuraxial preservative-free morphine after VD.

Acetaminopheninduced high anion gap metabolic acidosis: a potentially under-recognized consequence from a common medication.

While metabolic acidosis is one of the most common complications in patients with chronic kidney disease (CKD), there are several uncommon etiologies that are challenging to diagnose. Here, we describe a patient on peritoneal dialysis who developed high anion gap metabolic acidosis secondary to acquired 5-oxoprolinemia from acetaminophen use. While CKD is a known risk factor for developing this potentially serious complication, this case further highlights how 5-oxoproline accumulation can occur, even with therapeutic dosing of acetaminophen.

Patterns of acetaminophen toxicity among patients with low-risk serum concentrations.

In 2012, the Commission on Human Medicines mandated lowering the acetaminophen toxicity nomogram treatment threshold in the UK to 100 µg/ml at 4 h post-ingestion. The present study aim was to evaluate biochemical and liver toxicity patterns in patients who presented with acetaminophen overdose and had low serum acetaminophen concentrations (<150 µg/ml). Patients admitted to the emergency department with a clear history of acute acetaminophen overdose with or without other medication or ethanol were consecutively enrolled into this retrospective cohort study. Patients with serum acetaminophen concentration >150 µg/ml or an unknown ingestion time were excluded. Data were extracted from electronic medical records and are presented as mean ± SD or median (interquartile range). A total of 103 patients were included (median age, 17 [4-21] years) and 80 (78%) were female. The median ingested acetaminophen dose was 5000 (2850-7650) mg. At baseline, the median serum acetaminophen concentration was 42 (4.5-64.8) µg/ml, and median alanine aminotransferase and aspartate aminotransferase levels were 22 (17-28) and 27 (16-45) IU/L, respectively. Twenty patients were treated with acetylcysteine, with none developing adverse reactions. No patient developed hepatotoxicity, including patients with initial multiple product ingestion or other risk factors. Patients presenting with an acute acetaminophen overdose with acetaminophen level <150 µg/ml, including patients with other risk factors, are at low risk of hepatotoxicity.

Buchholzia Coriacea Up-Regulates Anti-Oxidant Genes and Represses Inflammatory and Apoptotic Genes in Post Administration of Sub-Chronic Dose of Acetaminophen Induced Hepato-Renal Toxicity in Male Wistar Rats

The aim of this research was to evaluate the possible renal and hepato-protective effects of ethanolic extract of Buchholzia coriacea seed and N-acetylcysteine, on gene expression in the liver and kidneys of Wistar rats subjected to post-treatment with sub-chronic dose of acetaminophen.

Corn-inspired high-density plasmonic metal-organic frameworks microneedles for enhanced SERS detection of acetaminophen

Effective monitoring of acetaminophen (APAP) dosage is crucial for preventing antipyretic abuse, ensuring therapeutic efficacy, and minimizing toxic effects. However, existing self-monitoring methods are limited. In this study, we designed a plasmonic microneedle (MN) sensor for real-time nondestructive monitoring of acetaminophen levels in dermal interstitial fluid (ISF) by employing a handheld Raman spectrometer. The fabricated MN sensor incorporated a high-density plasmonic MOFs known as HDPM, which unique structure of large specific surface area, specific pore structure as well as high density gold nanospheres packing enabled the excellent performance of selective ISF drug enrichment and surface-enhanced Raman scattering (SERS). The maximum electric field enhancement factor of the HDPM nanostructure could be calculated as 5.73 × 107. The developed HDPM@MNs was characterized with a core-shell type “soft on the outside and rigid on the inside” structure, which exhibited sufficient hardness and flexibility to penetrate the dermal tissue with little damage, and robust SERS enhancement effect in APAP detection without any interfering peaks. Through a hydrogel drug simulation experiment, the sensor demonstrated robust capabilities for acetaminophen enrichment and monitoring, exhibiting excellent stability and repeatability. The quantitative detection window spanned from 1 to 100 μM, with a low detection limit reaching 0.45 μM. Furthermore, by monitoring the concentration of acetaminophen in the interstitial fluid of rat skin at different doses and for different administration times, the HDPM@MNs can be used to determine the pharmacokinetics of acetaminophen in rats and the physiological characteristics associated with various dosage regimens. This work not only holds promise for drug monitoring but also provides a novel approach for nondestructive monitoring of other crucial low-abundance physiological markers.

Hepatoprotective effects of safranal on acetaminophen-induced hepatotoxicity in rats

Abstract This research aimed to explore the protective and therapeutic properties of safranal in mitigating inflammation and oxidative stress induced by elevated acetaminophen (APAP) doses in a rat model. The protective and therapeutic effects of safranal were determined by histopathologically and examining some biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), glutathione, glutathione peroxidase, catalase, malondialdehyde, interleukin-6, tumor necrosis factor-α, and interleukin-1β. Male Wistar–Albino rats were subject to random allocation, forming five groups, each comprising seven rats (n = 7) in the study. Group 1 was the control group. APAP was administered in Group 2 to induce hepatotoxicity. Rats in Groups 3, 4, and 5 received intraperitoneal injections of safranal at doses of 0.025, 0.05, and 0.1 mL/kg/day for 14 days, respectively. On the 15th day, to induce APAP-induced hepatotoxicity, four groups (Groups 2, 3, 4, and 5) acquired a single intraperitoneal injection of 600 mg/kg APAP. The presence of APAP-induced hepatotoxic effect was proven by elevated AST and ALT levels, which are typical biomarkers of liver function in addition to the demonstration of histopathological changes. The findings suggest that pre-treatment with safranal may offer a protective effect against hepatotoxicity by attenuating oxidative stress and the inflammatory response.

Acetaminophen used at therapeutic dosage causes significant changes in signaling pathways in mouse hearts

Acetaminophen (APAP) is a common over-the-counter medication that is used to treat pain and fever. It can be taken orally, topically, or intravenously and is considered a safe and effective drug when taken at therapeutic doses for a short amount of time. However, recent research suggests that APAP taken regularly can result in increased blood pressure, resulting in increased cardiovascular risk. Previous publications found that non-steroidal anti-inflammatory drugs (NSAIDs) resulted in increased Reactive Oxygen Species (ROS) in cardiomyocytes, resulting in cardiac dysfunction. Although APAP is not an NSAID, it is likely that APAP has similar effects. Our hypothesis is that regular usage of APAP increases ROS levels, leading to potential dysfunction in hearts and other organs. We treated five 6-month-old female mice with either water or acetaminophen dissolved in water for seven days. The concentration of acetaminophen that mice were given was 103 mg/kg/day, which is equivalent to a daily 500 mg dosage of acetaminophen in humans. The heart samples from these mice were homogenized in urea lysis buffer and then centrifuged to separate the supernatant from the pellet. After discarding the pellet, the proteins in the supernatant were discarded, and the pellet was treated with acetone overnight to allow the protein to precipitate. The supernatant was discarded, and the pellet was kept and denatured with tris(2-carboxyethyl) phosphine (TCEP) while incubating in a 55ºC dry bath, iodoacetamide was added to prevent disulfide bonds from forming, and acetone was added to the supernatant and left overnight to make proteins precipitate. After precipitation, the sample was centrifuged again to separate the supernatant from the pellet, and the pellet was saved while the supernatant was discarded. The pellet was resuspended and Tandem Mass Tags (TMT) label reagents were added to the samples, the samples quenched, and then combined and analyzed using mass spectroscopy (MS) after fractionating the samples using a Pierce High pH Reverse-Phase Peptide Fractionation kit (Thermofisher), then separated and eluted in liquid chromatography (LC) to determine any changes in the protein. LC/MS/MS data underwent a power analysis and Sequest-HT to compare samples to all mouse sequences. Target Decoy PSM was used to analyze and exclude decoy sequences from the samples, and Scaffold Q+ was used to quantify the peptides and proteins identified from the MS and LC data. Pathway analysis of the significant protein expression changes suggests antioxidant pathways, the ubiquitin-proteasome system, fatty acid oxidation, oxidative phosphorylation, and de novo purine synthesis and degradation. Proteasome assays were also conducted for the β5, β2, and β1 proteolytic subunits. There was a significant decrease in the β5 chymotrypsin-like activity in the hearts of APAP-treated mice compared to the control mice and no significant change in the β2 and β1 proteasome activity. Overall, these results show that mice treated with a therapeutic dosage of APAP regularly over the course of a week exhibited increased stress in the heart. NIEHS/Superfund Research Program (P42 ES004699). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice.

Introduction: Administration of high doses of acetaminophen (APAP) results in liver injury. Oxidative stress and iron overload play roles in the pathogenesis of APAP-induced hepatotoxicity. The present study assessed the potential hepatoprotective effects of phytic acid (PA), a natural antioxidant and iron chelator, on APAP-induced hepatotoxicity and the possible underlying mechanism through its effects on CYP2E1 gene expression, iron homeostasis, oxidative stress, and SIRT-1 expression levels. Methods: Twenty-four adult male albino mice were used in this study. Mice were divided into four groups (six mice in each group): control, APAP-treated, PA-treated and APAP + PA-treated groups. Liver function tests, serum and liver tissue iron load were evaluated in all the study groups. Hepatic tissue homogenates were used to detect oxidative stress markers, including malondialdehyde (MDA) and reduced glutathione (GSH). Histological hepatic evaluation and immunohistochemistry of SIRT-1 were performed. Quantitative real-time PCR was used for the assessment of CYP2E1 and SIRT-1 gene expressions. APAP-induced biochemical and structural hepatic changes were reported. Results: PA administration showed beneficial effects on APAP-induced hepatotoxicity through improvements in liver functions, decreased CYP2E1 gene expression, decreased serum and liver iron load, decreased MDA, increased GSH, increased SIRT-1 expression level and improvement in hepatic architecture. Conclusion: Conclusively, PA can be considered a potential compound that can attenuate acetaminophen-induced hepatotoxicity through its role as an iron chelator and antioxidant, as well as the up-regulation of SIRT-1 and down-regulation of CYP2E1.

AGE-RELATED CHARACTERISTICS OF GLUTATHIONE-DEPENDENT ENZYMES FUNCTIONING IN RATS UNDER CONDITIONS OF TOXIC INJURY BY ACETAMINOPHEN

Aim. The study is dedicated to evaluating the enzymatic activities of the glutathione system in liver cells of rats from different age groups under conditions of toxic injury caused by acetaminophen. In the experiments, rats of two age categories were used: young (138–150 days) and mature age (348–360 days). Mehods. Acute toxic injury from acetaminophen was induced by administering it per os at a dose of 1250 mg/kg of animal body weight during the last two days of the experiment. Results. Under conditions of simulated acute toxic injury by the medicinal xenobiotic acetaminophen in the livers of young and mature rats, a decrease was observed in glutathione-S-transferase, Se-dependent glutathione peroxidase, and glutathione reductase activities. A significant decrease in non-Se-glutathione peroxidase in liver cells is observed only in mature animals that were administered toxic doses of acetaminophen. The influence of the age component can be considered as one of the critically important factors in suppressing the functional activity of the glutathione-dependent enzymatic system, manifested by decreased activity of glutathione-S-transferase, non-Se-glutathione peroxidase, Se-dependent glutathione peroxidase and glutathione reductase under conditions of toxic injury caused by the medicinal xenobiotic acetaminophen. A more pronounced decrease in glutathione-dependent enzymes under conditions of acetaminophen intoxication is observed in animals aged 360 days. Cunclusion. The consequence of the established changes could be the disruption of acetaminophen biotransformation in Phase II involving the glutathione system, which can be considered as one of the risk factors for the development of drug-induced hepatotoxicity in different age groups.

Factors associated with pain intensity and analgesic use during inpatient rehabilitation for hip fracture.

Effective pain management is vital for hip fracture recovery, yet the factors influencing pain reporting and pain medication use during inpatient rehabilitation for hip fractures are not well understood. This observational study aimed to (a) determine how cognitive abilities, expressive and receptive language abilities, and age are related to average daily pain intensity and analgesic use and (b) how average daily pain intensity and analgesic use are related to length of stay and functional outcomes in rehabilitation. Data were retrospectively obtained from 163 patients recovering from unilateral trochanteric fractures of the femur. During the first week of rehabilitation, patients received a daily average of 1,147.8 ± 978 mg of acetaminophen and a morphine milligram equivalent of 15.3 ± 18.2. Multivariable regression revealed independent relationships between more intact general cognitive abilities (B = -0.40, 95% CI [-0.70, -0.11]), and older age (B = -0.41, 95% CI [-0.70, -0.11]) with lower average daily pain intensity. Higher average daily pain intensity (B = 0.97, 95% CI [0.75, 1.20]) was independently related to greater opioid use. The length of stay was shorter among patients administered higher daily doses of acetaminophen (B = 0.03, 95% CI [-0.05, -0.01]). Average daily pain intensity and analgesic use were not related to functional outcomes in multivariable models. These findings inform the considerations for assessing and treating pain during inpatient rehabilitation. Supplemental strategies for assessing pain in older patients and alternative pain mitigation strategies for patients with impaired cognitive abilities should be considered. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training.

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross-sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three-point bending and microcomputer tomography were measured in the femur. Follow-up experiments in human primary muscle cells were used to explore supra-physiological effects of ACE. Data were analyzed using a two-way ANOVA for treatment (ACE or placebo) and condition (exercise or non-exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment-by-condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated-AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho-4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post-exercise.

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Objectives To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. Methods This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. Findings FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. Conclusions This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. ClinicalTrials.gov Identifier NCT03224403 https://clinicaltrials.gov/ct2/show/NCT03224403

Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

Agreement Between a Colorimetric Assay and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Quantifying Paracetamol Plasma Concentrations.

Special populations, like geriatric patients, experience altered paracetamol pharmacokinetics (PK), complicating pain management. More PK research is essential to optimize paracetamol (acetaminophen) dosing. Yet, the reference method ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is not readily available. Therefore, we aimed to evaluate the agreement between UPLC-MS/MS and the more accessible colorimetric Roche acetaminophen (ACETA) assay in quantifying paracetamol plasma concentrations, to facilitate PK studies and therapeutic drug monitoring for pain management. Patient data and plasma samples were obtained from a prospective study including geriatric patients admitted to the geriatric wards. ACETA and UPLC-MS/MS assays were performed in two separate laboratories. Bland-Altman plot and Passing-Bablok regression were used to assess agreement. Accuracy was evaluated using the McNemar test for a threshold value of 10mg/L. Population PK modeling was employed to bridge PK data obtained from both methods (NONMEM 7.5). A total of 242 plasma sample pairs were available from 40 geriatric patients (age range, 80-95years). Paracetamol plasma concentrations from ACETA (median 9.8 [interquartile range 6.1-14.4] mg/L) and UPLC-MS/MS (9.5 [6.2-14.8] mg/L) did not differ significantly (P > 0.05). No significant proportional nor additive bias was observed between both assay methods. The classification accuracy (at threshold 10mg/L) was 85% (P = 0.414). The conversion factor between ACETA and UPLC-MS/MS was estimated at 1.06 (relative standard error 5%), yet with a 13.4% (relative standard error 23%) interindividual variability. ACETA assay showed no systematic bias in comparison with the UPLC-MS/MS assay in determining paracetamol exposure in geriatric blood samples despite the imprecision.

Hepatoprotective Effect of Merlot Grape Pomace Extract against Acetaminophen-Induced Damage in Mouse

This study investigated the benefits of Merlot grape pomace extract (EBUM) in experimental acetaminophen-induced intoxication. Swiss mice received the respective treatments for 7 days: Control (saline), Silymarin (100 mg/Kg), EBUM: 100 mg/Kg and 500 mg/Kg. On the seventh day, the acetaminophen control,Silymarin and EBUM received a single dose of acetaminophen 500 mg/kg. After 24 hours, the mice were sacrificed, the blood and liver were collected for analysis of serum transaminases (ALT and AST), bilirubin, hepatic markers of oxidative stress and histopathological analysis. EBUM was able to prevent acetaminophen-induced hepatic necrosis with a significant reduction (p&lt;0.0001) in ALT and AST, bilirubin, as well as a significant increase in hepatic GSH and CAT levels. The histological data are consistent with the transaminase results, showing less liver damage in the treated groups when compared to the acetaminophen group. The results allow us to infer that EBUM has a hepatoprotective effect against intoxication caused by acetaminophen in animal model, proving to be a therapeutic alternative in preventing drug-induced liver damage.