Hepatic Impairment Research Articles

Abstract 4135023: Effect of mild hepatic impairment on the pharmacokinetics of pelacarsen

Introduction: Pelacarsen, a hepatocyte-directed, N-acetyl galactosamine (GalNAc 3 )–conjugated antisense oligonucleotide, reduces plasma lipoprotein(a) levels by inhibiting apolipoprotein(a) translation. Pelacarsen uptake is mediated by GalNAc 3 binding to the hepatocyte-specific asialoglycoprotein receptor. Hypothesis: It is unknown whether hepatic impairment (HI) impacts pelacarsen uptake and systemic exposure. Aim: This single-dose, open-label, parallel-group, Phase 1 study (NCT05026996) assessed the pharmacokinetics (PK), safety, and tolerability of a single 80 mg subcutaneous dose of pelacarsen in participants with mild HI compared to healthy controls (normal hepatic function). Methods: Eight adults with prior liver cirrhosis and mild HI (Child-Pugh Class A) were matched for sex, age, and body weight with nine healthy controls. PK parameters (C max , AUC 0-72, AUC last , and AUC inf ) were determined using non-compartmental methods. Log-transformed PK parameters were analyzed using a statistical model with group and matching covariates as fixed effects. Least-square geometric means for each group and geometric mean ratios between participants with mild HI and healthy controls were extracted. Safety was also assessed. Results: Pelacarsen C max , AUC last, and AUC inf were, on average, 7%, 37%, and 50% higher, respectively, in participants with mild HI versus matched controls. All 90% confidence intervals around the HI versus healthy control geometric mean ratios included 1 ( Table ). The ranges of all PK parameters and estimated half-lives were similar between groups. In participants with mild HI, pelacarsen exposure approached the same level as controls after eight hours post-dose ( Figure ). No serious adverse events occurred. Conclusion(s): In participants with mild HI, pelacarsen was well tolerated. Mild HI had no significant effect on pelacarsen C max . The non-statistically significant transient increase in AUC was within the exposure range tested in the first-in-human study.

Advancements in breast cancer management: a comprehensive review of ribociclib combined with endocrine therapy

Background: In this review, the complicated landscape of breast cancer management is explored with a focus on the promising synergies between ribociclib and endocrine therapy. Ribociclib mainly acts as a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, which disrupts cell cycle progression necessary for tumor growth. This, in combination with endocrine therapy, aims to produce hormone receptor-positive breast cancers, which is a very relevant subtype with challenging therapeutics. Methods: A comprehensive review was conducted using multiple databases, PubMed, Embase, Scopus, Cochrane Library, and Web of Science, covering the period from January 1990 to May 2024. Results: Pharmacokinetic studies underscore the efficacy and tolerability of ribociclib, thus providing vital information for dose adjustments, particularly among patients with renal and hepatic impairments. Ribociclib’s value in extending progression-free survival and improving overall survival has been shown by clinical trials such as the MONALEESA series. Quality of life considerations and patient-reported outcomes from these trials indicate that ribociclib has a broader effect on the well-being of the patients. However, despite the success experienced by this drug in clinical practice, it still has some side effects, including hematologic toxicity, hepatotoxicity, and thromboembolism associated with it. Ribociclib resistance mechanisms are multifaceted mixtures comprising genetic variations or mutations, compensatory signaling pathways, and epigenomic changes. While overcoming resistance remains challenging, ongoing research seeks to reconcile. Conclusion: Ribociclib combined with endocrine therapy represents a significant advancement in breast cancer treatment, albeit with challenges that necessitate ongoing research and holistic patient care approaches.

Studying the association between single nucleotide polymorphisms of metabolizing enzymes and the therapeutic serum levels of calcineurin inhibitors in Egyptian liver transplant patients

BackgroundMany clinical variables might impact the pharmacokinetics of calcineurin inhibitors (CIs). Different alleles of cytochromes P450 (CYP)3A4/5 and drug transporter P-glycoprotein are the main variables. Other variables include relocated type, treatment duration after transplantation, age, sex, dietary consumption, medications used and renal or hepatic impairment. Tacrolimus and cyclosporine are two main CIs extensively used in organ transplantation. Both drugs are metabolized by CYP3A4 and CYP3A5 isoforms, and single-nucleotide polymorphisms in these genes have been displayed to influence CIs pharmacokinetics. Another important gene is the pregnane X receptor (PXR), which manages the statement of a variety of genes including CYP3A4 genes. PXR has a clinical significance in CIs metabolism. The liver is the essential site for CIs metabolism. A decreased clearance with a prolonged CIs half-life was occurred in patients with impaired liver compared with patients with normal liver function. The presence of different genetic and clinical factors that may affect calcineurin inhibitors trough levels will consequently affect their immunosuppressant effect after liver transplantation.PurposeThis study aims to determine the effect of different genetic polymorphisms in CYP3A4 1B rs2740574 and PXR A7635G rs6785049 and other clinical factors that may affect calcineurin inhibitors pharmacokinetics after liver transplantation.ResultsThe presence of T allele in CYP3A4 gene was associated with elevated DATLs with P values of 0.00, 0.00, 0.007 and 0.00 after tacrolimus doses 4, 30, 60 and 90, respectively. Regarding PXR gene, the presence of G allele was associated with elevated DATLs in cyclosporine. About 432 correlations were tested in both drugs. In CYP3A4 genotype CC, male sex was associated with elevated DATLs interpreted by strong positive correlations and statistically significant difference in all DATLs, except DATL 60 (P value 0.374). No strong association was found between low hemoglobin levels and DATLs in almost all the follow-up periods. There were many positive relations between increased total and direct bilirubin and increased DATLs.ConclusionsStudying the various genetics and clinical factors that may affect calcineurin inhibitors serum concentrations is very essential for successful treatment plans after organ transplantation. These different factors may interact with each other and these complicated interactions may complicate the patient’s conditions post-transplantation. Considering all these complicated interactions is very crucial in monitoring treatment plans, especially in the presence of other comorbidities or chronic diseases. More studies with large number of patients should be conducted to explore more consequences of these interacting variables of treatment plans of these patients and all studied parameters in this study should be considered while monitoring patients after transplantation.

Outcomes of Older Patients With Cardiogenic Shock Using the Impella Device - Insights From the Japanese Registry for Percutaneous Ventricular Assist Device (J-PVAD).

Aging has progressed in several regions of the world with more older patients experiencing acute cardiovascular disease. Impella is a percutaneous potent circulatory support device associated with substantial cost and potential device-related complications. We analyzed the Japanese nationwide registry, encompassing consecutive patients with cardiogenic shock using Impella. Among 5,718 patients treated between 2020 and 2022, we compared older patients (≥75 years) with younger patients. The primary outcome was the Kaplan-Meier estimated 30-day mortality, and the secondary outcome was Impella-related complications. The median age of the 5,718 patients was 69 (58-77) years, and 1,807 (31.6%) were older, with smaller body mass index, frequent acute coronary syndrome, and infrequent myocarditis. Comorbidities were frequently observed in older patients with a higher ejection fraction and less frequency of extracorporeal membrane oxygenation. Older patients had a higher 30-day mortality than younger patients (38.9% vs. 32.5%; P<0.0001). The 30-day mortality was statistically equivalent among older subsets (75-79 vs. 80-84 vs. ≥85 years). Device-related complications similarly occurred similarly among the older subsets, except for a modest increase in cardiac tamponade and limb ischemia. Older age, body mass index, myocarditis, prior arrhythmia, shock severity, renal and hepatic impairment, and limb ischemia were associated with 30-day mortality. The selected older patients using Impella exhibited modestly higher 30-day mortality with similar safety profiles. A longer follow up and optimal patient selection are important.

Population pharmacokinetics and exposure-response relationships of dostarlimab in primary advanced or recurrent endometrial cancer in part 1 of RUBY.

Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships. A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS). For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships. The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships.

Effect of Age, Sex, Renal Impairment and Hepatic Impairment on the Safety, Pharmacokinetics and Pharmacodynamics of Asundexian.

Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child-Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25mg. Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non-placebo-controlled group-stratification design. Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90% confidence intervals [CIs]) for the total asundexian area under the plasma concentration-time curve (AUC) for participants aged ≥65 to< 75 years versus ≥18 to <45 yearsand ≥75 to ≤80 years versus ≥18 to <45years were 1.257 (1.134-1.393) and 1.288 (1.158-1.433), respectively, and for females versus males, it was 1.084 (0.995-1.182). Point estimates (geometric LS means) (90% CIs) for unbound AUC in participants in estimated glomerular filtration rate (eGFR) categories G2 (60-89 mL/min/1.73 m2), G3 (30-59 mL/min/1.73 m2) and G4 (15-29 mL/min/1.73 m2) versus control were 1.003 (0.698-1.443), 0.791 (0.550-1.138) and 0.882 (0.606-1.285), respectively, and in participants with ESKD on dialysis-free day versus control was 0.597 (0.406-0.877). There was no effect of the dialysis procedure on the pharmacokinetics of asundexian. In participants deemed Child-Pugh class A and Child-Pugh class B, geometric LS means (90% CIs) for unbound AUC were 0.834 (0.597-1.164) and 1.143 (0.810-1.612), respectively, when compared to participants with normal liver function. Activated partial thromboplastin time (aPTT) was assessed as a pharmacodynamic variable of interest. Geometric mean maximum aPTT prolongation as a ratio to baseline after administration of asundexian 25 mg ranged from 1.45 to 1.55 in all age and sex groups, 1.49-1.59 in the control and eGFR G2 to G4 groups, 1.38-1.54 in the control and ESKD groups on dialysis and dialysis-free day and 1.38-1.89 in the healthy control and liver impairment groups. The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected. EudraCT 2022-000196-38 and 2020-000626-25.

Population pharmacokinetic modeling of zavegepant, a calcitonin gene-related peptide receptor antagonist, in healthy adults and patients with migraine.

Zavegepant (ZAVZPRET™) is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist available for acute treatment of migraine in adults. A population pharmacokinetic analysis was performed to describe zavegepant plasma concentration-time course, characterize bioavailability, and identify covariates affecting zavegepant exposure. The model was developed and validated using data from 10 phase I clinical studies, wherein zavegepant was administered intravenously, intranasally, or orally to healthy adults and patients with migraine. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. A three-compartment model with first-order elimination from the central compartment, and sequential zero- and first-order absorption best described the observed plasma concentration-time course of zavegepant. Bioavailability was 5.1% and 0.65% for intranasal and oral treatment, respectively; absorption rate constants were 5.8 and 0.8 h-1, respectively. Body weight-based empirical allometric scaling was applied using standard exponents (0.75 for clearance and 1 for volume of distribution). Age (range 18-71 years), race, ethnicity, sex, renal function, and co-administration of oral contraceptives or sumatriptan did not significantly change zavegepant pharmacokinetics. Moderate hepatic impairment (Child-Pugh score 7-9) or co-administration of rifampin decreased elimination clearance of oral zavegepant by ~40%. The zavegepant population pharmacokinetic model adequately characterized zavegepant concentration-time profiles, the bioavailability of intranasal and oral zavegepant, as well as the effect of intrinsic and extrinsic factors on zavegepant pharmacokinetics.

Protective Effects of Lemna minor Linn. On Hepatic and Cognitive Impairments in Acetaminophen Induced Hepatic Encephalopathy in Rats

Aim: Lemna minor Linn., an aquatic plant, is a promising novel therapeutic agent that has been traditionally used in ethnobotanical practices as an ecofriendly supplement for the management of various ailments. This study involves the evaluation of ethanolic extract of Lemna minor Linn. against Paracetamol-induced Hepatic Encephalopathy using in vitro and in vivo Models. Methods: The acute oral toxicity study of the ethanolic extract of Lemna minor (EELM) was conducted following the OECD-425 guidelines over a 14-day period. A total of nine animals were used for this toxicity assessment. The EELM was tested in Paracetamol(PCM)-induced bioactivation animal model at two different dosages 200 and in comparison with silymarin as a standard compound. The In vivo experimental study was conducted using Sprague Dawley rats which was divided into 5 groups each group containing 6 animals so the total no of animals used in the study was 30 animals. The treatment groups included: normal control ( ), 100mg/kg silymarin (standard) and the EELM of two different doses of 200 and , p.o were administered to rats 10 hr before paracetamol ( ) treatment. Rats were orally administered their respective doses every day for total 30days. Paracetamol-induced oxidative liver damage disrupted normal levels of liver enzymes, total protein, and bilirubin, while also depleting antioxidant reserves. This oxidative stress was strongly associated with paracetamol toxicity, leading to a marked depletion of glutathione (GSH) and impairing both memory and cognitive function in the animals. Behavioral parameters are performed to evaluate the effect of drugs on cognitive behaviour of animals. Morris water maze test was performed to study how animals learn and remembers the spatial information relying on distal cues to locate the hidden platform in an opaque water. Additionally, elevated plus maze was performed to measures the anxious behaviour of rats, the criterion was tested based on the conflict between rats innate instincts to explore new environment and avoid open, well-lit areas. The potential protective effects of EELM was evaluated by measuring serum enzyme levels and antioxidants status in the liver and brain, further histopathological analysis was performed respectively. Results: The acute toxicity study did not report any mortality or toxicity signs in animals. PCM toxicity led to a statistically increase in the liver and body weight, along with brain water content. The PCM-intoxicated group exhibited a marked reduction in the level of superoxide dismutase (SOD) and glutathione (GSH) in the brain and liver, as well as an increase in lipid peroxidation and serum biomarkers (AST, ALT, ALP, and total bilirubin). EELM significantly ( ) reduced liver injury by inhibiting ALT, AST and ALP levels in serum. SOD, GSH and MDA liver content were significantly ( ) elevated by EELM, compared to PCM treated rats. Comparing the treatment and induced group, the treated group successfully recovered the activity of antioxidant levels and also been acknowledged for restored liver functioning by alleviating oxidative stress and also GSH level in brain was significantly increased by EELM and preserved the histology of brain, which was chronically produced over a period of 30 days. Conclusion: The findings of this investigation indicate the traditional use of Lemna minor in hepatoprotection and neuroprotection by regulating oxidative stress and mitigating reactive oxygen species (ROS). The insights gained from this research contribute to the development of novel therapeutic agents and paves the way for further studies on Lemna minor to enhance health outcomes, particularly in the management of neurodegenerative diseases.

Risk factors associated with post-tuberculosis sequelae: a systematic review and meta-analysis

Post-tuberculosis (TB) sequelae present a significant challenge in the management of TB survivors, often leading to persistent health issues even after successful treatment. Identifying risk factors associated with post-TB sequelae is important for improving outcomes and quality of life of TB survivors. This systematic review and meta-analysis aims to identify risk factors associated with long-term physical sequelae among TB survivors. We systematically searched Medline, Embase, PROQUEST, and Scopus for studies on long-term physical sequelae among TB survivors up to December 12, 2023. The primary outcome of interest was to quantify risk factors of long-term physical sequelae (i.e., respiratory, hepatic, hearing, neurological, visual, renal, and musculoskeletal sequelae). We included all forms of TB patients who experienced long-term physical sequelae. We used narrative synthesis for risk factors reported once and random-effect meta-analysis for primary outcomes with two or more studies. Findings were presented with odds ratios (OR) and 95% confidence intervals (CI). Publication bias was assessed using funnel plots and Egger regression, and heterogeneity was examined with a Galbraith radial plot. The protocol was registered on Prospero (CRD42021250909). A total of 73 articles from 28 countries representing 31,553TB-treated patients were included in the narrative synthesis, with 64 of these studies included in the meta-analysis. Risk factors associated with post-TB lung sequelae include older age (OR=1.62, 95% CI: 1.07-2.47), previous TB treatment history (OR=3.43, 95% CI: 2.37-4.97), smoking (OR=1.41, 95% CI: 1.09-1.83), alcohol consumption (OR=1.84, 95% CI: 1.04-3.25), smear-positive pulmonary TB diagnosis (OR=3.11, 95% CI: 1.77-6.44), and the presence of radiographic evidence of pulmonary lesions at the commencement of treatment (OR=2.04, 95% CI: 1.07-3.87). Risk factors associated with post-TB liver injury included pre-existing hepatitis (OR=2.41, 95% CI: 1.16-6.08), previous TB treatment (OR=2.64, 95% CI: 1.22-6.67), hypo-albuminemia (OR=2.10, 95% CI: 1.53-2.88), HIV co-infection (OR=2.72, 95% CI: 1.66-4.46), and CD4 count <200mm3 in HIV-infected individuals (OR=2.03, 95%CI: 1.26-3.27). Risk factors associated with post-TB hearing loss include baseline hearing problems (OR=1.72, 95% CI: 1.30-2.26), and HIV co-infection (OR=3.02, 95% CI: 1.96-4.64). This systematic review and meta-analysis found that long-term physical post-TB sequelae including respiratory, hepatic, and hearing impairment were associated with a range of socio-demographic, behavioral, and clinical factors. Identification of these risk factors will help to identify patients who will benefit from interventions to reduce the burden of suffering from post-TB treatment. Healy Medical Research Raine Foundation, the Australian National Health and Medical Research Council, and Curtin University Higher Degree Research Scholarship fund the study.

Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease. The addition of eltrombopag to immunosuppressive therapy (IST) improves the response rate and response quality of SAAs, but its hepatotoxicity is concerning. Avatrombopag (AVA), another small-molecule thrombopoietin receptor agonist without hepatotoxicity, has unknown efficacy in SAA treatment. This retrospective study aimed to assess the efficacy and safety of AVA, a small-molecule thrombopoietin receptor agonist, when added to IST in SAA patients. A total of 42 patients treated with IST and AVA were compared to a historical cohort of 84 patients receiving IST alone, utilizing propensity score matching. The median age was 31.5 (6.0-67.0) years old in Group A and 26 (16.0-45.0) years old in Group B. At 3 months, Group A showed higher complete response (CR) and overall response (OR) rates than Group B (CR: 19.0% vs. 4.8%, P = 0.024; OR: 54.8% vs. 39.3%, P=0.145). Higher CR and OR rates were also found at 6 months in Group A than in Group B (CR 31.0% vs. 14.3%, P=0.145; OR 71.4% vs. 51.2%, P=0.048). In multivariate analysis of Group A, a shorter interval from disease onset to anti-thymocyte globulin (ATG) treatment (≤6 months) (P=0.005) predicted better responses rate at 6 months. Event free survival was also improved in Group A (60.7% vs. 49.6%). AVA was well-tolerated, with no hepatic injury observed during treatment, even in those with pre-existing hepatic impairment. The addition of AVA to IST improves both the response rate and response quality in SAA patients while ensuring safety.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Low rates of haemorrhagic stroke, not increased by age, renal/hepatic impairment, concomitant anti-platelet use and high CHA2DS2-VASc scores, in the 4-year follow-up of ETNA-AF-Europe

Abstract Background Balancing the risks of stroke and bleeding is necessary to optimise oral anticoagulation use in clinical practice. Concerns remain over the increased bleeding risk in patients receiving NOACs, and long-term safety data in this population are limited. Purpose To report annualised rates of haemorrhagic stroke in various sub-populations of patients with atrial fibrillation (AF) treated with edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe, a post-authorisation, observational study conducted across 776 sites from 10 European countries, assessed the risks and benefits of edoxaban use in patients with AF. Here, we present the annualised event rates of haemorrhagic stroke during the 4-year follow-up, that occurred overall (on-/off-edoxaban) and on-edoxaban, including sub-populations stratified by age, renal impairment, hepatic impairment, chronic concomitant antiplatelet use and CHA2DS2-VASc score. Patient characteristics were collected at baseline and annualised event rates were reported for outcomes. Results A total of 13,164 patients were included in the full analysis set. Baseline characteristics are reported in Table 1. The overall and on-edoxaban annualised haemorrhagic stroke rates were low (number of events, % [95% confidence interval]: 36, 0.1 [0.05;0.11] and 31, 0.1 [0.05;0.10] respectively). The overall haemorrhagic stroke rates remained low in subgroups stratified by age (&amp;lt;65 years: 4, 0.1 [0.00;0.11]; ≥65–75 years: 13, 0.1 [0.04;0.13]; ≥75 years: 19, 0.1 [0.05;0.12]), renal impairment (yes: 23, 0.1 [0.05;0.13]; no: 12, 0.1 [0.03;0.11]), hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 35, 0.1 [0.06;0.11]), concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.16]; no: 34, 0.1 [0.05;0.11]) and CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 28, 0.1 [0.06;0.12]; high [&amp;gt;4]: 7, 0.1 [0.03;0.18]) (Figure). Likewise, on-edoxaban haemorrhagic stroke rates were low irrespective of age (&amp;lt;65 years: 3, &amp;lt;0.1 [0.00;0.010; ≥65–75 years: 12, 0.1 [0.04;0.13]; ≥75 years: 16, 0.1 [0.04;0.12]); renal impairment (yes: 20, 0.1 [0.05;0.12]; no: 10, 0.1 [0.02;0.10]); hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 30, 0.1 [0.05;0.11]); chronic concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.18; no: 29, 0.1[0.05;0.10]) or CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 25, 0.1 [0.05;0.12]; High [&amp;gt;4]: 6, 0.1 [0.02;0.17]) (Figure). Conclusions The overall and on-edoxaban annualised rates of haemorrhagic stroke were low and were not increased by non-modifiable risk factors such as age, renal/hepatic impairment, concomitant antiplatelet use and high CHA2DS2-VASc scores during the 4-year follow-up. The overall annualised rates on-edoxaban in ETNA-AF-Europe registry are quite comparable with incidence rates reported in the literature in age-stratified populations (incidence/100 person-years: 55-64 years: 0.06 [0.04-0.07]; 65-74 years: 0.1 [0.09-0.1]; 75-84 years 0.2 [0.1-0.2]).Baseline Characteristics

Salvianolic acid B improves the microcirculation in a mouse model of sepsis through a mechanism involving the platelet receptor CD226.

Salvianolic acid B (SalB) demonstrates diverse clinical applications, particularly in cardiovascular and cerebral protection. This study primarily investigated the effects of SalB on sepsis. The model of sepsis via caecal ligation puncture (CLP) was established in male C57BL/6 mice. Therapeutic effects of SalB on hepatic and pulmonary injury, inflammatory responses and microcirculatory disturbances in sepsis were evaluated. Platelet aggregation and adhesion were measured via flow cytometry and an adhesion test. After overexpression of platelet-related activating molecules by 293T cells, the efficient binding of SalB and platelet CD226 molecules was further evaluated. Finally, neutralizing antibody experiments were used to assess the mechanism of SalB in alleviating the progression of sepsis. SalB mitigated hepatic and pulmonary impairments, reduced inflammatory cytokine levels and enhanced mesenteric microvascular blood flow in septic mice. SalB enhanced CLP-induced reduction of platelet count and platelet pressure cumulative volume. SalB reduced platelet adhesion to endothelial cells and platelet aggregation to leukocytes. A high binding efficiency was observed between SalB and the platelet adhesion molecule CD226. Ex vivo, interactions between SalB and platelets from CD226-knockout mice were markedly decreased. In vivo administration of CD226 neutralizing antibodies significantly delayed disease progression and enhanced mesenteric microcirculation in septic mice. In our murine model of sepsis, treatment with SalB improved the microcirculatory disturbance and hindered the progression of sepsis by inhibiting platelet CD226 function. Our results suggest SalB is a promising therapeutic approach to the treatment of sepsis.

Plasma protein binding of arsenic species in acute promyelocytic leukemia patients and their relationships with hepatic and renal function

ABSTRACT Objectives Percentage protein binding (%PB) of arsenic species in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide remains unclear. It can be different depending on the status of hepatic or renal function. Methods This study obtained steady-state blood samples from normal APL patients and those with hepatic or renal impairment. %PB of inorganic arsenic (iAs), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) was determined by analyzing free and total plasma concentrations using ultrafiltration method by HPLC-HG-AFS. Results There is a linear relationship between free and total plasma concentrations for iAs (r2 = 0.952), MMAV (r2 = 0.603), and DMAV (r2 = 0.945). For patients with normal hepatic and renal function, mean %PB was as follows: iAs at 26.7 ± 14.3%, MMAV at 53.3 ± 11.9%, and DMAV at 24.7 ± 7.8%. %PB decreased in patients with renal impairment, with MMAV and DMAV showing statistically significant differences (p < 0.05 for MMAV, p < 0.01 for DMAV). No significant differences in %PB between normal and hepatic impairment group were observed. Conclusion Free arsenic species fraction can be estimated by total concentration. DMAV and iAs present low %PB, while MMAV exhibits a relatively high %PB in plasma. Level of %PB is more likely to be affected by renal function and age.

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

Risks and outcomes among coronavirus disease 2019 patients admitted to Assiut University Hospital

Introduction The clinical characteristics present with coronavirus disease 2019 (COVID-19) encompasses asymptomatic to severe disease and mortality. Clinicians need to detect patients whose risk of illness progression and unfavorable outcomes is high. Aim To evaluate potential risk factors affecting the severity and outcome of coronavirus infection in patients admitted to Assiut University. Patients and methods From October 2021 to October 2022, Assiut University Hospital served as the site of this observational analytical cross-sectional single-centered study. A full medical history, examination, radiographic, and laboratory investigations were performed on patients. Results The primary risk variables for mortality of COVID-19 patients include a greater mean age (73.61 ± 10.51) (P value&lt;0.001). Individuals with chronic kidney disease (P value=0.005), and liver cirrhosis (P value&lt;0.001). Those unvaccinated against COVID-19 the (P value = 0.004). Laboratory findings can be used as a predictor of infection severity as higher median white blood cell count (P value=0.044), lower median lymphocytic count (P value=0.028), higher serum ferritin (P value=0.02). Radiologically, a significant higher mean computed tomography severity score percentage is noticed among died patients (16.61 ± 4.55%) (P value&lt;0.001). Conclusion Advanced age, patients with renal or hepatic impairment, patients with lower lymphocytic counts or with higher computed tomography severity score are linked to a worse clinical course and outcome among COVID-19 patients who were admitted to Assiut University Hospital. Trial registration ClinicalTrials.gov. NCT04860232.

Potential role of host autophagy in Clonorchis sinensis infection.

An in vivo mouse model of Clonorchis sinensis (C. sinensis) infection with or without the administration of autophagy inhibitor chloroquine (CQ) stimulation was established to assess the possible involvement of autophagic response during C. sinensis infection. Abnormal liver function was observed at 4, 6, and 8weeks post-infection, as indicated by elevated levels of ALT/GPT, AST/GOT, TBIL, and α-SMA in the infected groups. These findings indicated that C. sinensis infection activated autophagy, as shown by a decreased LC3II/I ratio and accumulated P62 expression in infected mice. Interestingly, CQ administration exhibited dual and opposing effects during the infection. In the early stage of infection, the engagement of CQ appeared to mitigate symptoms by reducing inflammation and fibrotic responses. However, in the later stage of infection, CQ might contribute to parasite survival by evading autophagic targeting, thereby exacerbating hepatic impairment and worsening liver fibrosis. Autophagy in liver was suppressed throughout the infection. These observations attested that C. sinensis infection triggered autophagy, and highlighted a complex role for CQ, with both protective and detrimental effects, in the in vivo process of C. sinensis infection.

Exosome-related gene identification and diagnostic model construction in hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI) may cause severe hepatic impairment, acute hepatic insufficiency, and multiorgan system collapse. Exosomes can alleviate HIRI. Therefore, this study explored the role of exosomal-related genes (ERGs) in HIRI using bioinformatics to determine the underlying molecular mechanisms and novel diagnostic markers for HIRI. We merged the GSE12720, GSE14951, and GSE15480 datasets obtained from the Gene Expression Omnibus (GEO) database into a combined gene dataset (CGD). CGD was used to identify differentially expressed genes (DEGs) based on a comparison of the HIRI and healthy control cohorts. The impact of these DEGs on HIRI was assessed through gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). ERGs were retrieved from the GeneCards database and prior studies, and overlapped with the identified DEGs to yield the set of exosome-related differentially expressed genes (ERDEGs). Functional annotations and enrichment pathways of these genes were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Diagnostic models for HIRI were developed using least absolute shrinkage and selection operator (LASSO) regression and support vector machine (SVM) algorithms. Key genes with diagnostic value were identified from the overlap, and single-sample gene-set enrichment analysis (ssGSEA) was conducted to evaluate the immune infiltration characteristics. A molecular regulatory interaction network was established using Cytoscape software to elucidate the intricate regulatory mechanisms of key genes in HIRI. Finally, exosome score (Es) was obtained using ssGSEA and the HIRI group was divided into the Es_High and Es_Low groups based on the median Es. Gene expression was analyzed to understand the impact of all genes in the CGD on HIRI. Finally, the relative expression levels of the five key genes in the hypoxia-reoxygenation (H/R) model were determined using quantitative real-time PCR (qRT-PCR). A total of 3810 DEGs were identified through differential expression analysis of the CGD, and 61 of these ERDEGs were screened. Based on GO and KEGG enrichment analyses, the ERDEGs were mainly enriched in wound healing, MAPK, protein kinase B signaling, and other pathways. GSEA and GSVA revealed that these genes were mainly enriched in the TP53, MAPK, TGF[Formula: see text], JAK-STAT, MAPK, and NFKB pathways. Five key genes (ANXA1, HNRNPA2B1, ICAM1, PTEN, and THBS1) with diagnostic value were screened using the LASSO regression and SVM algorithms and their molecular interaction network was established using Cytoscape software. Based on ssGSEA, substantial variations were found in the expression of 18 immune cell types among the groups (p < 0.05). Finally, the Es of each HIRI patient was calculated. ERDEGs in the Es_High and Es_Low groups were enriched in the IL18, TP53, MAPK, TGF[Formula: see text], and JAK-STAT pathways. The differential expression of these five key genes in the H/R model was verified using qRT-PCR. Herein, five key genes were identified as potential diagnostic markers. Moreover, the potential impact of these genes on pathways and the regulatory mechanisms of their interaction network in HIRI were revealed. Altogether, our findings may serve as a theoretical foundation for enhancing clinical diagnosis and elucidating underlying pathogeneses.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Pritelivir and Its Metabolites.

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration-time curve from time 0 to infinity (AUC0- inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA-acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.

Concentration-QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study.

This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor. Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity). Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild). There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.