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41. Influence of OATP1B1 and OATP1B3 mutations and glomerular filtration rate on trough serum digoxin concentration in the Chinese population: A prospective cohort study. Full Text available with Trip Pro

Influence of OATP1B1 and OATP1B3 mutations and glomerular filtration rate on trough serum digoxin concentration in the Chinese population: A prospective cohort study. Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G (...) >A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher

2019 Medicine

42. Digoxin Use and Associated Adverse Events Among Older Adults. (Abstract)

Digoxin Use and Associated Adverse Events Among Older Adults. Over the past 2 decades, guidelines for digoxin use have changed significantly. However, little is known about the national-level trends of digoxin use, hospitalizations for toxicity, and subsequent outcomes over this time period.To describe digoxin prescription trends, we conducted a population-level, cohort study using data from IQVIA, Inc.'s National Prescription Audit (2007-2014) for patients aged ≥65 years. Further (...) , in a national cohort of Medicare fee-for-service beneficiaries aged ≥65 years in the United States, we assessed temporal trends of hospitalizations associated with digoxin toxicity and the outcomes of these hospitalizations between 1999 and 2013.From 2007 through 2014, the number of digoxin prescriptions dispensed decreased by 46.4%; from 8,099,856 to 4,343,735. From 1999 through 2013, the rate of hospitalizations with a principal or secondary diagnosis of digoxin toxicity decreased from 15 to 2 per 100,000

2019 American Journal of Medicine

43. Digoxin Use and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction. (Abstract)

Digoxin Use and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction. Heart failure is a leading cause for hospital readmission. Digoxin use may lower this risk in patients with heart failure with reduced ejection fraction (HFrEF), but data on contemporary patients receiving other evidence-based therapies are lacking.Of the 11,900 patients with HFrEF (ejection fraction ≤45%) in Medicare-linked OPTIMIZE-HF, 8401 were not on digoxin, of whom 1571 received discharge prescriptions (...) for digoxin. We matched 1531 of these patients with 1531 not receiving digoxin by propensity scores for digoxin use. The matched cohort (n = 3062; mean age, 76 years; 44% women; 14% African American) was balanced on 52 baseline characteristics. We assembled a second matched cohort of 2850 patients after excluding those with estimated glomerular filtration rate <15 mL/min/1.73 m2 and heart rate <60 beats/min. Hazard ratios (HRs) and 95% confidence intervals (CIs) for digoxin-associated outcomes were

2019 American Journal of Medicine

44. Digoxin-mortality: randomized vs. observational comparison in the DIG trial. Full Text available with Trip Pro

comparison.Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. (...) Digoxin-mortality: randomized vs. observational comparison in the DIG trial. The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons

2019 European Heart Journal Controlled trial quality: uncertain

45. Treatment of fetal supraventricular tachycardia by intra-amniotic administration of digoxin. (Abstract)

Treatment of fetal supraventricular tachycardia by intra-amniotic administration of digoxin. Fetal arrhythmias occur in as many as 1- 3% of pregnancies1 . Supraventricular tachycardia (SVT) accounts for about 66-90% of fetal tachyarrhythmia2 . First-line therapy has not been determined in randomized trials, but digoxin has been considered the first-choice drug. Flecainide and sotalol have been advocated as second-choice drugs, though flecainide might be more effective as a first-line treatment3

2019 Ultrasound in Obstetrics and Gynecology

46. Intra-amniotic digoxin for feticide between 21 and 30 weeks of gestation: a prospective study. (Abstract)

gestational age was 24+2  weeks (range 21+0 -30+0 ), with 29 (49.2%) beyond 24+0  weeks of gestation. Fetal cardiac activity arrest was achieved in 55/59 cases (93.2%). Normal maternal ECG recordings were noted in all cases. Mean serum digoxin levels 6 and 10 hours after injection were in the therapeutic range (1.3 ± 0.7 ng/l and 1.24 ± 0.49 ng/l, respectively) and below the toxic level (2 ng/l). Extramural delivery following digoxin did not occur. There were no cases of chorioamnionitis.Intra-amniotic (...) Intra-amniotic digoxin for feticide between 21 and 30 weeks of gestation: a prospective study. Intra-amniotic injection of digoxin is a well-known method for feticide before inducing a termination of pregnancy (TOP) at 17-24 weeks of gestation. Information on its effectiveness when administered after 24 weeks of gestation is limited. This study evaluated the efficacy of intra-amniotic digoxin injection for inducing fetal demise within 18-24 hours, at 21-30 weeks of gestation, and its

2019 BJOG

47. Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects. Full Text available with Trip Pro

Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects. Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover (...) trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent

2019 Clinical pharmacokinetics Controlled trial quality: uncertain

48. A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin. (Abstract)

A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin. A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100 mg sitagliptin (OAT3; CLR ), 500 mg metformin (several renal (...) transporters; CLR ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80

2019 Clinical pharmacology and therapeutics Controlled trial quality: uncertain

49. Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia. Full Text available with Trip Pro

Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia. 27872497 2018 06 05 2018 11 13 1476-5551 31 3 2017 03 Leukemia Leukemia Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia. 755-759 10.1038/leu.2016.341 Cerella C C Laboratoire de Biologie Moléculaire et (...) Apoptosis Regulatory Proteins 0 BCL2 protein, human 0 Cardenolides 0 Cardiac Glycosides 0 Myeloid Cell Leukemia Sequence 1 Protein 0 Proto-Oncogene Proteins c-bcl-2 0 UNBS 1450 0 bcl-X Protein IM Apoptosis drug effects Apoptosis Regulatory Proteins metabolism Cardenolides pharmacology Cardiac Glycosides pharmacology Cell Line, Tumor Humans Leukemia, Myeloid, Acute drug therapy metabolism Myeloid Cell Leukemia Sequence 1 Protein metabolism Proto-Oncogene Proteins c-bcl-2 metabolism U937 Cells bcl-X

2016 Leukemia

50. Two cases of cardiac glycoside poisoning from accidental foxglove ingestion Full Text available with Trip Pro

08 Canada CMAJ 9711805 0820-3946 0 Antidotes 73K4184T59 Digoxin AIM IM Aged Antidotes administration & dosage Arrhythmias, Cardiac chemically induced Digitalis drug effects poisoning Digoxin blood toxicity Electrocardiography Female Humans Hyperkalemia Male Nausea Vomiting 2016 2 10 6 0 2016 2 10 6 0 2017 3 31 6 0 ppublish 26858347 cmaj.150676 10.1503/cmaj.150676 PMC4938686 Pharmacology. 2008;82(3):221-7 18810246 Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005490 17054261 Prog Cardiovasc Dis (...) Two cases of cardiac glycoside poisoning from accidental foxglove ingestion 26858347 2017 03 30 2018 11 13 1488-2329 188 10 2016 Jul 12 CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne CMAJ Two cases of cardiac glycoside poisoning from accidental foxglove ingestion. 747-50 10.1503/cmaj.150676 Janssen Renée M RM Departments of Medicine (Janssen, Ovakim) and Emergency Medicine (Berg), University of British Columbia; British Columbia Drug and Poison

2016 CMAJ : Canadian Medical Association Journal

51. Transcriptome and Metabolite analysis reveal candidate genes of the cardiac glycoside biosynthetic pathway from Calotropis procera Full Text available with Trip Pro

Transcriptome and Metabolite analysis reveal candidate genes of the cardiac glycoside biosynthetic pathway from Calotropis procera Calotropis procera is a medicinal plant of immense importance due to its pharmaceutical active components, especially cardiac glycosides (CG). As genomic resources for this plant are limited, the genes involved in CG biosynthetic pathway remain largely unknown till date. Our study on stage and tissue specific metabolite accumulation showed that CG's were maximally (...) engineering and regulation of cardiac glycosides biosynthesis pathway genes.

2016 Scientific reports

52. L30A mutation of phospholemman mimics effects of cardiac glycosides in isolated cardiomyocytes Full Text available with Trip Pro

L30A mutation of phospholemman mimics effects of cardiac glycosides in isolated cardiomyocytes To determine if mutations introduced into phospholemman (PLM) could increase the level of PLM-Na,K-ATPase (NKA) binding, we performed scanning mutagenesis of the transmembrane domain of PLM and measured Förster resonance energy transfer (FRET) between each mutant and NKA. We observed an increased level of binding to NKA for several PLM mutants compared to that of the wild type (WT), including L27A (...) , L30A, and I32A. In isolated cardiomyocytes, overexpression of WT PLM increased the amplitude of the Ca2+ transient compared to the GFP control. The Ca2+ transient amplitude was further increased by L30A PLM overexpression. The L30A mutation also delayed Ca2+ extrusion and increased the duration of cardiomyocyte contraction. This mimics aspects of the effect of cardiac glycosides, which are known to increase contractility through inhibition of NKA. No significant differences between WT and L30A PLM

2016 Biochemistry

53. Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells Full Text available with Trip Pro

Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB

2016 Acta pharmacologica Sinica

54. Cardiac Glycosides Activate the Tumor Suppressor and Viral Restriction Factor Promyelocytic Leukemia Protein (PML) Full Text available with Trip Pro

Cardiac Glycosides Activate the Tumor Suppressor and Viral Restriction Factor Promyelocytic Leukemia Protein (PML) Cardiac glycosides (CGs), inhibitors of Na+/K+-ATPase (NKA), used clinically to treat heart failure, have garnered recent attention as potential anti-cancer and anti-viral agents. A high-throughput phenotypic screen designed to identify modulators of promyelocytic leukemia protein (PML) nuclear body (NB) formation revealed the CG gitoxigenin as a potent activator of PML. We

2016 PloS one

55. Regulation of myofibroblast differentiation by cardiac glycosides Full Text available with Trip Pro

Regulation of myofibroblast differentiation by cardiac glycosides Myofibroblast differentiation is a key process in pathogenesis of fibrotic diseases. Cardiac glycosides (ouabain, digoxin) inhibit Na(+)-K(+)-ATPase, resulting in increased intracellular [Na(+)]-to-[K(+)] ratio in cells. Microarray analysis suggested that increased intracellular [Na(+)]/[K(+)] ratio may promote the expression of cyclooxygenase-2 (COX-2), a critical enzyme in the synthesis of prostaglandins. Given antifibrotic (...) effects of prostaglandins through activation of protein kinase A (PKA), we examined if cardiac glycosides stimulate COX-2 expression in human lung fibroblasts and how they affect myofibroblast differentiation. Ouabain stimulated a profound COX-2 expression and a sustained PKA activation, which was blocked by COX-2 inhibitor or by COX-2 knockdown. Ouabain-induced COX-2 expression and PKA activation were abolished by the inhibitor of the Na(+)/Ca(2+) exchanger, KB-R4943. Ouabain inhibited transforming

2016 American Journal of Physiology - Lung Cellular and Molecular Physiology

56. Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma Full Text available with Trip Pro

glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC. (...) Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression

2016 Oncotarget

57. Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation Full Text available with Trip Pro

are traditionally used to regulate intracellular calcium by inhibiting the Na+/K+ ATPase to control cardiac contractility. Herein, we report that multiple cardiac glycoside compounds, including digoxin, are able to inhibit TGF-β-induced fibronectin expression at low nanomolar concentrations without undesirable cell toxicity. We found this inhibition to hold true for multiple fibroblast cell lines. Using real-time qPCR, we determined that digoxin prevented induction of multiple CAF markers. Furthermore, we (...) Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation The tumor microenvironment, primarily composed of myofibroblasts, directly influences the progression of solid tumors. Through secretion of growth factors, extracellular matrix deposition, and contractile mechanotransduction, myofibroblasts, or cancer-associated fibroblasts (CAFs), support angiogenesis and cancer cell invasion and metastasis. The differentiation

2016 Oncotarget

58. Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity Full Text available with Trip Pro

Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play

2016 Journal of natural products

59. Cardiac glycosides display selective efficacy for STK11 mutant lung cancer Full Text available with Trip Pro

Cardiac glycosides display selective efficacy for STK11 mutant lung cancer Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer (...) effects on STK11 mutant lung cancer cell lines. Restoring STK11 function reduced the efficacy of CGs. Clinically relevant doses of digoxin decreased the growth of STK11 mutant xenografts compared to wild type STK11 xenografts. Increased cellular stress was associated with the STK11-specific efficacy of CGs. Inhibiting ROS production attenuated the efficacy of CGs, and STK11-AMPK signaling was important in overcoming the stress induced by CGs. Taken together, these results show that STK11 mutation

2016 Scientific reports

60. Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay Full Text available with Trip Pro

Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data (...) suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications

2016 Journal of the American Chemical Society

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