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Clinical and Translational Science Dec 2023Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF). Decreased... (Review)
Review
Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF). Decreased nitric oxide (NO) availability, sGC desensitization to NO, sGC deficiency, and reduced cyclic guanosine monophosphate (cGMP) signaling are potential contributing factors for HF disease progression. Vericiguat works via stimulation of sGC in the critical NO-sGC-cGMP pathway. Vericiguat is primarily metabolized by glucuronidation via uridine diphosphate-glucuronosyltransferase (UGT) isoforms UGT1A1 and UGT1A9. Urinary excretion and renal clearance of vericiguat are low. No intrinsic factor had a clinically relevant effect on vericiguat exposure. Vericiguat has low drug-drug interaction potential with no clinically relevant pharmacokinetic or pharmacodynamic interactions observed with warfarin, digoxin, aspirin, or sacubitril/valsartan. The global phase III study VICTORIA included patients with HFrEF who had a recent HF hospitalization or intravenous diuretic treatment for HF. Treatment with vericiguat on top of standard of care resulted in a 10% relative reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for HF. Vericiguat was well-tolerated with low incidence of symptomatic hypotension and syncope compared to placebo. Given its positive benefit-risk profile, vericiguat is an important option for high-risk patients with HFrEF who are already on guideline-directed medical therapy and had recent worsening of HF. Future efforts to develop additional effective therapies are needed to further reduce morbidity and mortality in patients with HF.
Topics: Humans; Heart Failure; Treatment Outcome; Translational Science, Biomedical; Stroke Volume; Vasodilator Agents
PubMed: 37997225
DOI: 10.1111/cts.13677 -
Clinical Pharmacokinetics Jan 2024Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight,...
BACKGROUND AND OBJECTIVE
Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals.
METHODS
This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery.
RESULTS
The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [-0.94, 3.2]) or the diet group (0.94 µg h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 µg h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.
CONCLUSIONS
Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.
Topics: Humans; Gastric Bypass; Digoxin; Obesity; Obesity, Morbid; Diet; Weight Loss; ATP Binding Cassette Transporter, Subfamily B, Member 1
PubMed: 37993699
DOI: 10.1007/s40262-023-01320-9 -
Chinese Medicine Nov 2023Xinyang Tablet (XYT) has emerged as a potential intervention to counter sepsis-induced myocardial dysfunction (SMID) by influencing macrophage autophagy and M2...
Xinyang tablet ameliorates sepsis-induced myocardial dysfunction by regulating Beclin-1 to mediate macrophage autophagy and M2 polarization through LncSICRNT1 targeting E3 ubiquitin ligase TRAF6.
OBJECTIVE
Xinyang Tablet (XYT) has emerged as a potential intervention to counter sepsis-induced myocardial dysfunction (SMID) by influencing macrophage autophagy and M2 polarization. This study aimed to unravel the underlying mechanism of XYT in sepsis-induced myocardial dysfunction (SIMD).
METHODS
A microarray analysis was employed to explore sepsis-related changes, and bioinformatics analysis was used to predict lncRNAs binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). This studio utilized SIMD mouse models induced by lipopolysaccharide (LPS) injection, followed by treatments involving varied doses of XYT, digoxin (positive control), or si-LncSICRNT1. After seven days, evaluations encompassing mouse hair/mental state/diet/weight were measured, and cardiac function via echocardiography were conducted. Myocardial tissue changes were observed using hematoxylin-eosin staining. Additionally, bone marrow-derived macrophages (BMDMs) subjected to LPS for M1 polarization were treated with oe-LncSICRNT1, si-TRAF6 and their negative control, XYT, or autophagy inhibitor 3-Methyladenine (3-MA) (positive control). RT-qPCR and Western blot analyses were employed to assess LncSICRNT1, TRAF6, Beclin-1, LC3II/LC3I, and p62 levels. Immunohistochemistry and flow cytometry were used for M1/M2 polarization markers, while enzyme-linked immunosorbent assay (ELISA) gauged inflammatory factor levels. Interaction between TRAF6 and LncSICRNT1 was probed using RNA pull-down and RNA immunoprecipitation (RIP) assays.
RESULTS
Chip analysis obtained 1463 differentially expressed lncRNAs, including LINC01550 (LncSICRNT1). Further prediction indicated that LncSICRNT1 was highly likely to directly bind to TRAF6. XYT treatment in LPS-induced SIMD mice led to notable enhancements in sleep/hair/diet/activity, increased weight/left ventricular end-diastolic diameter (LVEDd)/LV ejection fraction (LVEF)/LV fraction shortening (LVFS). These improvements were associated with elevated LncSICRNT1 expression and decreased TRAF6 protein levels, culminating in reduced myocardial inflammatory responses and improved cardiac function. Notably, XYT was found to suppress macrophage M1 polarization, while enhancing M2 polarization, ultimately benefitting cardiac function via LncSICRNT1 modulation. Furthermore, the study revealed LncSICRNT1 modulated Beclin-1 ubiquitination and restrained macrophage autophagy by targeting TRAF6 expression.
CONCLUSION
The study highlights XYT's potential to ameliorate LPS-induced SIMD by elevating LncSICRNT1 expression, influencing TRAF6 expression, and regulating Beclin-1 ubiquitination. These actions collectively inhibit macrophage autophagy and foster M1/M2 polarization, contributing to cardiac function improvement.
PubMed: 37919806
DOI: 10.1186/s13020-023-00832-7 -
World Journal of Stem Cells Sep 2023Heart failure (HF) is a global health problem characterized by impaired heart function. Cardiac remodeling and cell death contribute to the development of HF. Although...
BACKGROUND
Heart failure (HF) is a global health problem characterized by impaired heart function. Cardiac remodeling and cell death contribute to the development of HF. Although treatments such as digoxin and angiotensin receptor blocker drugs have been used, their effectiveness in reducing mortality is uncertain. Researchers are exploring the use of adipose-derived mesenchymal stem cell (ADMSC) exosomes (Exos) as a potential therapy for HF. These vesicles, secreted by cells, may aid in tissue repair and regulation of inflammation and immune responses. However, further investigation is needed to understand the specific role of these vesicles in HF treatment.
AIM
To investigate the mechanism of extracellular vesicles produced by ADMSC s in the treatment of HF.
METHODS
Exogenous surface markers of ADMSCs were found, and ADMSCs were cultured.
RESULTS
The identification of surface markers showed that the surface markers CD44 and CD29 of adipose-derived stem cells (ADSCs) were well expressed, while the surface markers CD45 and CD34 of ADSCs were negative, so the cultured cells were considered ADSCs. Western blotting detected the Exo surface marker protein, which expressed CD63 protein but did not express calnexin protein, indicating that ADSC-derived Exos were successfully extracted.
CONCLUSION
The secretion of MSCs from adipose tissue can increase ATP levels, block cardiomyocyte apoptosis, and enhance the heart function of animals susceptible to HF. The inhibition of Bax, caspase-3 and p53 protein expression may be related to this process.
PubMed: 37900939
DOI: 10.4252/wjsc.v15.i9.897 -
Case Reports in Neurological Medicine 2023While the systemic effects of digoxin have been studied, limited data exist on the effects of neuraxial administration. Prior case reports document how digoxin and...
While the systemic effects of digoxin have been studied, limited data exist on the effects of neuraxial administration. Prior case reports document how digoxin and lidocaine share indistinguishable vials and were inadvertently stocked together in spinal and epidural anesthesia kits, necessitating a need for further implementation of safety measures. Here, we report the poor progression and brain death of a postpartum woman after accidental administration of intrathecal digoxin during a routine elective cesarean section (C-section). It is imperative that quality improvement and safety measures are taken to avoid the recurrence of this medical error.
PubMed: 37899764
DOI: 10.1155/2023/4034919 -
Toxicology Reports Dec 2023is a toxic plant containing cardiac glycosides throughout all its parts, thereby posing severe health risks upon ingestion. The clinical manifestations of oleander...
INTRODUCTION
is a toxic plant containing cardiac glycosides throughout all its parts, thereby posing severe health risks upon ingestion. The clinical manifestations of oleander poisoning closely resemble those of digoxin toxicity, encompassing a of gastrointestinal symptoms, neuropsychiatric disorders, and cardiac disturbances. This scientific case report describes a case of accidental intoxication resulting from the consumption of an oleander leaves infusion misidentified as bay laurel leaves.
CASE REPORT
An 84-year-old patient consumed an oleander leaves infusion, and after four hours experienced gastrointestinal symptoms. He contacted the poison control center (PCC) and was advised to go to the emergency department (ED). Upon arrival, the patient presented stable vital signs without cardiac irregularities. The PCC recommended the administration of activated charcoal, vigilant monitoring, including electrocardiography (ECG). Subsequent ECGs assessments revealed the presence of third-degree atrioventricular block; in consultation with the PCC, digoxin-specific antibodies and external pacing were necessary. The patient was discharged on the eighth day in good hemodynamic condition, and outpatient follow-up visits showed clinical stability.
DISCUSSION
This study offers insights for the management of similar cases. The limitations of conventional assays in measuring oleander cardiac glycosides were observed, emphasizing reliance on clinical evaluation. The patient's trajectory, remaining asymptomatic despite severe ECG changes post-ingestion, underscores the importance of prolonged clinical monitoring.
PubMed: 37885923
DOI: 10.1016/j.toxrep.2023.10.010 -
Clinical Science (London, England :... Oct 2023In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+... (Review)
Review
In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+ sensitivity in vascular smooth muscle cells. This review focuses on the potential implication of Na,K-ATPase-dependent intracellular signaling pathways in severe vascular disorders; ischemic stroke, familial migraine, and arterial hypertension. We propose similarity in the detrimental Na,K-ATPase-dependent signaling seen in these pathological conditions. The review includes a retrospective proteomics analysis investigating temporal changes after ischemic stroke. The analysis revealed that the expression of Na,K-ATPase α isoforms is down-regulated in the days and weeks following reperfusion, while downstream Na,K-ATPase-dependent cSrc kinase is up-regulated. These results are important since previous studies have linked the Na,K-ATPase-dependent cSrc signaling to futile recanalization and vasospasm after stroke. The review also explores a link between the Na,K-ATPase and migraine with aura, as reduced expression or pharmacological inhibition of the Na,K-ATPase leads to cSrc kinase signaling up-regulation and cerebral hypoperfusion. The review discusses the role of an endogenous cardiotonic steroid-like compound, ouabain, which binds to the Na,K-ATPase and initiates the intracellular cSrc signaling, in the pathophysiology of arterial hypertension. Currently, our understanding of the precise control mechanisms governing the Na,K-ATPase/cSrc kinase regulation in the vascular wall is limited. Understanding the role of vascular Na,K-ATPase signaling is essential for developing targeted treatments for cerebrovascular disorders and hypertension, as the Na,K-ATPase is implicated in the pathogenesis of these conditions and may contribute to their comorbidity.
Topics: Humans; Sodium-Potassium-Exchanging ATPase; Retrospective Studies; Muscle, Smooth, Vascular; Hypertension; Sodium; Stroke; Ischemic Stroke; Migraine Disorders
PubMed: 37877226
DOI: 10.1042/CS20220796 -
Netherlands Heart Journal : Monthly... Feb 2024Digoxin-specific antibodies (digoxin-Fabs) are of value in the treatment of a strongly suspected or a known, potentially life-threatening digoxin toxicity. These... (Review)
Review
Digoxin-specific antibodies (digoxin-Fabs) are of value in the treatment of a strongly suspected or a known, potentially life-threatening digoxin toxicity. These antibodies are not registered for use in Europe; therefore Dutch hospital pharmacies are not allowed to keep them in stock. In the Netherlands, digoxin-Fabs are stored in a national calamity stock of emergency medicines at the National Institute for Public Health and the Environment. In the case of a medical emergency, digoxin-Fabs are available after contact with the Dutch Poisons Information Centre. Recent studies have shown that the dose of digoxin-Fabs required to effectively treat digoxin toxicity is lower than previously thought. In this article, we present the adjusted digoxin-Fab dosing strategy currently recommended by the Dutch Poisons Information Centre ( www.vergiftigingen.info ). This new dose titration strategy is safe and effective and has a cost-saving side-effect.
PubMed: 37861975
DOI: 10.1007/s12471-023-01814-y -
Cureus Sep 2023Renal dysfunction is a common complication among patients with congestive heart failure (CHF) and can significantly impact their management, especially when medications...
INTRODUCTION
Renal dysfunction is a common complication among patients with congestive heart failure (CHF) and can significantly impact their management, especially when medications like digoxin are involved. The clearance of digoxin is closely tied to the glomerular filtration rate (GFR), which suggests that the safety and efficacy of digoxin may vary with renal function. Therefore, this study aimed to assess the potential effects of digoxin on renal function in patients diagnosed with CHF at a tertiary hospital in the Asir region of Saudi Arabia.
METHODS
A retrospective study examined the records of 30 CHF patients treated with digoxin. Renal function markers like estimated GFR (eGFR), creatinine, blood urea nitrogen (BUN), albumin, and urine levels were compared before and after digoxin treatment. Liver enzymes and other relevant parameters were also examined. A statistical analysis using t-tests was conducted to evaluate the changes in renal function indicators before and after digoxin treatment.
RESULTS
The mean eGFR decreased significantly from 65.4 ± 8.9 mL/min/1.73m before digoxin to 57.7 ± 7.8 mL/min/1.73m after (p = 0.001). Creatinine, BUN, albumin, and urine levels showed no significant changes. Digoxin significantly increased aspartate aminotransferase (AST) from 34.5 ± 11.6 U/L to 53.8 ± 14.6 U/L (p = 0.002), alanine aminotransferase (ALT) from 38.5 ± 12.6 U/L to 55.3 ± 17.6 U/L (p = 0.013), and creatine kinase from 117.7 ± 22.5 U/L to 133.9 ± 15.8 U/L (p = 0.012). Hemoglobin decreased significantly from 12.8 ± 1.4 g/dL to 12.1 ± 1.4 g/dL (p = 0.034). No significant changes occurred in myoglobin, troponin, bilirubin, platelets, potassium, calcium, or chloride levels. Effects on kidney function did not differ significantly by gender or age, except blood urea nitrogen was higher in patients over 50 years (8.3 ± 2.3 vs. 5.6 ± 2.7 mg/dL, p = 0.015).
CONCLUSION
This study suggests digoxin may adversely affect renal function in CHF patients, as evidenced by reduced eGFR. However, the small retrospective design limits definitive conclusions. Further prospective research with larger samples is warranted to elucidate digoxin's renal effects in CHF patients.
PubMed: 37854741
DOI: 10.7759/cureus.45419