-
JAMA Jun 2023Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown.
OBJECTIVE
To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022.
INTERVENTIONS
Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase.
MAIN OUTCOMES AND MEASURES
The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days.
RESULTS
Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group.
CONCLUSIONS AND RELEVANCE
Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03661411.
Topics: Female; Humans; Male; Middle Aged; Cerebral Hemorrhage; Fibrinolytic Agents; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Tissue Plasminogen Activator; Treatment Outcome; Drug Therapy, Combination; Thrombolytic Therapy; Administration, Intravenous; Clopidogrel; Aspirin; Follow-Up Studies; Aged; Recovery of Function
PubMed: 37367978
DOI: 10.1001/jama.2023.7827 -
Cell Host & Microbe Feb 2024Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how...
Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how this impacts intestinal homeostasis remains unclear. Herein, using clinical cohorts and aspirin-treated mice, we identified an intestinal microbe, Parabacteroides goldsteinii, whose growth is suppressed by aspirin. Mice supplemented with P. goldsteinii or its BA metabolite, 7-keto-lithocholic acid (7-keto-LCA), showed reduced aspirin-mediated damage of the intestinal niche and gut barrier, effects that were lost with a P. goldsteinii hdhA mutant unable to generate 7-keto-LCA. Specifically, 7-keto-LCA promotes repair of the intestinal epithelium by suppressing signaling by the intestinal BA receptor, farnesoid X receptor (FXR). 7-Keto-LCA was confirmed to be an FXR antagonist that facilitates Wnt signaling and thus self-renewal of intestinal stem cells. These results reveal the impact of oral aspirin on the gut microbiota and intestinal BA metabolism that in turn modulates gastrointestinal homeostasis.
Topics: Mice; Animals; Aspirin; Bile Acids and Salts; Gastrointestinal Microbiome; Receptors, Cytoplasmic and Nuclear; Homeostasis
PubMed: 38237593
DOI: 10.1016/j.chom.2023.12.015 -
Annual Review of Pathology Jan 2024Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is... (Review)
Review
Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of -acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.
Topics: Humans; Animals; Acetaminophen; Chemical and Drug Induced Liver Injury; Apoptosis; Acetylcysteine; Autophagy
PubMed: 38265880
DOI: 10.1146/annurev-pathmechdis-051122-094016 -
Best Practice & Research. Clinical... Mar 2024Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It... (Review)
Review
Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It disproportionally affects low-resource countries. Appropriate identification of individuals at increased risk and prevention of the disease and its complications remain healthcare and research priorities, and the investigation of potential interventions to prevent preeclampsia has driven much of the obstetric research in recent decades. In this article, we review the scientific literature on the topic, highlighting established benefits and remaining questions regarding different non-pharmacological and pharmacological strategies, including exercise, the timing of birth, aspirin and calcium use, among others, as well as potential novel therapies under investigation.
Topics: Pregnancy; Female; Child; Humans; Pre-Eclampsia; Aspirin; Pregnancy Complications
PubMed: 38373378
DOI: 10.1016/j.bpobgyn.2024.102481 -
Nature Communications Mar 2024Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain...
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.
Topics: Animals; Humans; Male; Mice; Acetaminophen; Asialoglycoprotein Receptor; Endoplasmic Reticulum Stress; Fibrosis; Liver; Liver Cirrhosis
PubMed: 38459023
DOI: 10.1038/s41467-024-46135-9 -
Cureus Oct 2023Acetaminophen, or paracetamol, ranks among the most extensively utilized analgesic and antipyretic medications globally. The administration of acetaminophen to... (Review)
Review
Acetaminophen, or paracetamol, ranks among the most extensively utilized analgesic and antipyretic medications globally. The administration of acetaminophen to individuals with underlying liver disease has long sparked concerns regarding the potential risk of hepatotoxicity. However, the available literature and recommendations consider it a safe option in all forms of liver diseases and is deemed safe when used at recommended doses. This article aims to offer a concise review of the pharmacokinetics, toxicity profile, and the intricate considerations surrounding the safety of acetaminophen in patients with liver disease. By delving into the liver-acetaminophen interactions, we seek to provide a nuanced perspective on the use of acetaminophen in this critical patient population.
PubMed: 38022064
DOI: 10.7759/cureus.47071