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Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.
Fontenla, A, López-Gil, M, Tamargo-Menéndez, J, Matía-Francés, R, Salgado-Aranda, R, Rey-Blas, JR, Miracle-Blanco, Á, Mejía-Martínez, E, Pastor-Fuentes, A, Toquero-Ramos, J, et al
Revista espanola de cardiologia (English ed.). 2020;(5):368-375
Abstract
INTRODUCTION AND OBJECTIVES Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Identifier: NCT03718273.
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Effects of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the steady-state pharmacokinetics of digoxin in healthy adult subjects.
Liu, F, Vessey, L, Wenning, L, Connolly, S, Buckland, M, Johnson-Levonas, AO, Denker, A, Wagner, JA, Lai, E
Journal of clinical pharmacology. 2010;(7):823-8
Abstract
Laropiprant, a prostaglandin D(2) receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful.
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Effects of digoxin on muscle reflexes in normal humans.
Janssen, C, Lheureux, O, Beloka, S, Adamopoulos, D, Naeije, R, van de Borne, P
European journal of applied physiology. 2009;(5):581-6
Abstract
Blockade of the skeletal muscle Na(+)-K(+)-ATPase pump by digoxin could result in a more marked hyperkaliema during a forearm exercise, which in turn could stimulate the mechano- and metaboreceptors. In a randomized, double-blinded, placebo-controlled, and cross-over-design study, we measured mean blood pressure (MBP), heart rate (HR), ventilation (V(E)), oxygen saturation (SpO(2)), muscle sympathetic nerve activity (MSNA), venous plasma potassium and lactic acid during dynamic handgrip exercises, and local circulatory arrest in 11 healthy subjects. Digoxin enhanced MBP during exercise but not during the post-handgrip ischemia and had no effect on HR, V(E), SpO(2), and MSNA. Venous plasma potassium and lactic acid were also not affected by digoxin-induced skeletal muscle Na(+)-K(+)-ATPase blockade. We conclude that digoxin increased MBP during dynamic exercise in healthy humans, independently of changes in potassium and lactic acid. A modest direct sensitization of the muscle mechanoreceptors is unlikely and other mechanisms, independent of muscle reflexes and related to the inotropic effects of digoxin, might be implicated.
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Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.
Gurley, BJ, Swain, A, Barone, GW, Williams, DK, Breen, P, Yates, CR, Stuart, LB, Hubbard, MA, Tong, Y, Cheboyina, S
Drug metabolism and disposition: the biological fate of chemicals. 2007;(2):240-5
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Abstract
Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
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Human intestinal P-glycoprotein activity estimated by the model substrate digoxin.
Larsen, UL, Hyldahl Olesen, L, Guldborg Nyvold, C, Eriksen, J, Jakobsen, P, Østergaard, M, Autrup, H, Andersen, V
Scandinavian journal of clinical and laboratory investigation. 2007;(2):123-34
Abstract
OBJECTIVE P-glycoprotein (Pgp) plays a part in the intestinal uptake of xenobiotics and has been associated with susceptibility to ulcerative colitis. The aim of this study was to examine Pgp activity in relation to age, gender, medical treatment (rifampicin or ketoconazole) and the multidrug resistance (MDR1) gene single nucleotide polymorphisms (SNPs) G2677T and C3435T using the model drug digoxin. MATERIAL AND METHODS Pgp activity was estimated from the pharmacokinetics of orally administered digoxin in blood samples from 32 healthy subjects. MDR1 gene expression in duodenal biopsies was monitored by real-time quantitative RT-PCR (RQ-PCR) and Western blot analyses. MDR1 SNPs were determined by PCR-restriction fragment length polymorphism (PCR-RFLP). The effect of medical treatment was tested by open, randomized, cross-over treatment with rifampicin and ketoconazole. RESULTS Rifampicin treatment resulted in increased Pgp activity, duodenal MDR1 mRNA expression and Pgp detection compared with that in the control group (p<0.05 for all), Pgp activity being associated with duodenal MDR1 mRNA level (p<0.05). Individuals homozygous for the 3435 wild-type allele (CC) showed higher Pgp activity (p<0.05), whereas SNP 2677 apparently did not affect Pgp activity. No variation in Pgp in relation to age or gender was found. CONCLUSIONS Our data confirm that rifampicin increases Pgp activity, by increasing MDR1 mRNA and Pgp levels. Moreover, we found that the wild-type allele of the synonymous polymorphism of MDR1 position 3435 confers a higher Pgp activity. These data support other findings suggesting an effect of Pgp on treatment response and disease susceptibility.
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Verapamil versus digoxin and acute versus routine serial cardioversion for the improvement of rhythm control for persistent atrial fibrillation.
Hemels, ME, Van Noord, T, Crijns, HJ, Van Veldhuisen, DJ, Veeger, NJ, Bosker, HA, Wiesfeld, AC, Van den Berg, MP, Ranchor, AV, Van Gelder, IC
Journal of the American College of Cardiology. 2006;(5):1001-9
Abstract
OBJECTIVES The VERDICT (Verapamil Versus Digoxin and Acute Versus Routine Serial Cardioversion Trial) is a prospective, randomized study to investigate whether: 1) acutely repeated serial electrical cardioversions (ECVs) after a relapse of atrial fibrillation (AF); and 2) prevention of intracellular calcium overload by verapamil, decrease intractability of AF. BACKGROUND Rhythm control is desirable in patients suffering from symptomatic AF. METHODS A total of 144 patients with persistent AF were included. Seventy-four (51%) patients were randomized to the acute (within 24 h) and 70 (49%) patients to the routine serial ECVs, and 74 (51%) patients to verapamil and 70 (49%) patients to digoxin for rate control before ECV and continued during follow-up (2 x 2 factorial design). Class III antiarrhythmic drugs were used after a relapse of AF. Follow-up was 18 months. RESULTS At baseline, there were no significant differences between the groups, except for beta-blocker use in the verapamil versus digoxin group (38% vs. 60%, respectively, p = 0.01). At follow-up, no difference in the occurrence of permanent AF between the acute and the routine cardioversion groups was observed (32% [95% confidence intervals (CI)] 22 to 44) vs. 31% [95% CI 21 to 44], respectively, p = NS), and also no difference between the verapamil- and the digoxin-randomized patients (28% [95% CI 19 to 40] vs. 36% [95% CI 25 to 48] respectively, p = NS). Multivariate Cox regression analysis revealed that lone digoxin use was the only significant predictor of failure of rhythm control treatment (hazard ratio 2.2 [95% CI 1.1 to 4.4], p = 0.02). CONCLUSIONS An acute serial cardioversion strategy does not improve long-term rhythm control in comparison with a routine serial cardioversion strategy. Furthermore, verapamil has no beneficial effect in a serial cardioversion strategy.
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Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin.
Mueller, SC, Uehleke, B, Woehling, H, Petzsch, M, Majcher-Peszynska, J, Hehl, EM, Sievers, H, Frank, B, Riethling, AK, Drewelow, B
Clinical pharmacology and therapeutics. 2004;(6):546-57
Abstract
BACKGROUND AND OBJECTIVE St John's wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St John's wort formulations and doses with digoxin. METHODS A randomized, placebo-controlled, parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7-day loading phase with digoxin was followed by 14 days of comedication with placebo or one of 10 St John's wort products varying in dose and formulation. The pharmacokinetics of digoxin was determined before comedication and on day 14 of comedication. RESULTS Comedication comprised traditionally used Hypericum products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had no significant interaction with digoxin nor did hyperforin-free extract (Ze 117) or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g). However, comedication with the high-dose hyperforin-rich extract LI 160 resulted in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0-24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a reduction in digoxin plasma concentration at 24 hours after previous dosing (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24) of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95% CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to -10). Two grams of Hypericum powder with half the hyperforin content resulted in a less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max) (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). CONCLUSIONS The interaction of St John's wort and digoxin varies within St John's wort preparations and doses and seems to be correlated with the dose, particularly of hyperforin.
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Cross-sectional study of heart failure therapy with angiotensin converting enzyme inhibitors and digoxin.
Mahmood, SA, Hussein, GM, Hamza, EA
Saudi medical journal. 2004;(8):1060-5
Abstract
OBJECTIVE The aim of the present study is to show a better short-term (2 weeks) clinical improvement in patients with heart failure (HF) who are receiving angiotensin converting enzyme inhibitors (ACEIs) (with or without digoxin) when compared to the standard therapy excluding ACEIs. METHODS The study was conducted in Al-Gamhuria Teaching Hospital, Aden, Yemen, from January to July 2003. In this study, 78 patients with HF were enrolled into 3 therapeutic groups (ACEIs alone, ACEI and digoxin and digoxin alone) and their responses within 2 weeks were recorded. Exclusion criteria were as follows: thyroid disorders, gastrointestinal disturbances (diarrhea, malabsorption), electrolyte unbalanced (unless corrected) and insufficient data. Serum creatinine was measured at the beginning and after 10 days. In addition, the patients' body weight and age were recorded. Criteria for a complete improvement within 2 weeks were the occurrence of the following: 1) The relief of pulmonary congestion, 2) Decrement in heart rate to less than 74 +/- 5, 3) Disappearance of the lower limb edema, and 5) Recorded positive electroencephalogram change. Partial amelioration was recognized if only 2 or 3 of the preceding criteria were observed. RESULTS Nine patients received digoxin alone, while 40 patients were treated with ACEIs and digoxin. Treatment with ACEIs without digoxin was observed in 29 patients. The discrepancy between the number of patients was necessitated by the need of patients with HF. This last category of treatment regimen produced better clinical improvement (complete with 10.1%, partial with 24.3%) compared to the digoxin group without ACEI (complete 2.5% or partial 5.1%). Nevertheless, the addition of digoxin to an ACEI increased this ratio (17.8% for complete and 28.2% for partial improvement). A 49.3% increase in serum creatinine was observed after 10 days in 25 HF patients, who were randomly selected and followed up (the baseline concentration was 99.75 +/- 9.9 umol/L, while the level after 10 days was 148.97 +/- 19.8 umol/L, p=0.005). CONCLUSION We confirmed that short-term use of ACEI regimens has a superior effect on the therapy of HF (34.4% complete and partial response) as compared to the therapy of not using ACEI (7.6% had a complete and partial response). The combination of ACEI and digoxin has resulted in the best outcome (46% had a complete and partial response). However, we also noticed a significant rise in serum creatinine by 49% concomitant with the use of ACEI (the baseline concentration was 99.75 +/- 9.9 um/L, while the level after 10 days was 148.97 +/- 19.8 umol/L, p=0.005).
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Hypothalamic digoxin-mediated model for Parkinson's disease.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(4):515-36
Abstract
The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na(+)-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.
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[Clinical observation of congestive heart failure treated by integrated traditional Chinese and Western medicine].
Jian, M
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2002;(7):542, 544