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Introduction: We aimed to assess the impact of digoxin use following left ventricular assist device (LVAD) implantation on clinical outcomes. Methods: Patients implanted with continuous flow LVADs at a single academic medical center and survived to initial hospital discharge were included in the analysis ( n = 346). Clinical events were captured at a maximum of 2 years of follow up. Digoxin use was defined as 30-day continuous use post-LVAD. Negative binomial regression and Kaplan-Meier method were used to assess the association between digoxin use and clinical outcomes. Results: Mean age of the cohort was 56 years (±13) and 23% (79/346) were female sex. Digoxin was used in 144 patients (41.6%) for a median of 268 days (IQR 154, 616). Digoxin use was associated with a significant reduction in cumulative incidence of gastrointestinal bleeding (GIB) (15% vs 26%, p = 0.004). After adjusting for age, hypertension, post-operative hemoglobin, RDW, potassium, and GFR, and use of angiotensin receptor/neprilysin inhibitor, there remained a significant 47% reduction in GIB incidence in patients treated with digoxin. There was no significant difference in cumulative incidence in right ventricular failure (RVF) between the two groups. There was no difference in overall 2-year survival between groups. Conclusions: Digoxin use was associated with reduction in GIB events, but not in RVF or mortality. Further studies are needed to confirm these findings and to investigate optimal timing and patient population.

Abstract: Heart failure (HF) is a common cause of morbimortality with different etiopathogenesis and prognosis between men and women. This review provides a brief overview of gender-based differences in response to pharmacological therapies of heart failure with or without reduced ejection fraction (EF). It focuses on the differences in therapy outcomes with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), angiotensin neprilysin inhibitors (ARNI), beta-adrenergic blockers, mineralocorticoid/ aldosterone receptor antagonists, diuretics, ivabradine and digoxin. The baseline data originate from randomised controlled trials (RCTs) and large registries. We conclude that current guidelines recommending similar therapeutic approaches for both men and women are appropriate, while additional consideration should be given to different approaches regarding the use of ARBs, ACEi, and digoxin. Based on the available data, the ARBs might be considered a first-line therapy of HR for women instead of ACEi. Moreover, female patients should have stricter digoxin monitoring due to higher sensitivity and increased risk of complications. Finally, women are underrepresented in current clinical trials, and therefore future trials should aim to balance the gender recruitment disparity allowing sub-group analysis and comparisons between genders to guide individualised therapeutic strategies and appropriately targeted preventative steps.

As one of the key components in model‐informed drug discovery and development, physiologically‐based pharmacokinetic (PBPK) modeling linked with in vitro‐to‐in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug–drug interactions (DDIs) on drug‐metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P‐glycoprotein (Pgp, ABCB1)‐mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis‐Menten constant (K m) to be intrinsic, in vitro‐to‐in vivo scaling factors for maximal Pgp‐mediated efflux rate (J max) were optimized based on the clinically observed results without co‐administration of Pgp inhibitors. For Pgp inhibitors, PBPK models utilized the reported in vitro values of Pgp inhibition constants (K i), 1.0 μM for itraconazole and 2.0 μM for verapamil. Overall, the PBPK modeling sufficiently described Pgp‐mediated DDIs between these substrates and inhibitors with the prediction errors of less than or equal to ±25% in most cases, suggesting a reasonable IVIVE for Pgp kinetics in the clinical DDI results. The modeling results also suggest that Pgp kinetic parameters of both the substrates (K m and J max) and the inhibitors (K i) are sensitive to Pgp‐mediated DDIs, thus being key for successful DDI prediction. It would also be critical to incorporate appropriate unbound inhibitor concentrations at the site of action into PBPK models. The present results support a quantitative prediction of Pgp‐mediated DDIs using in vitro parameters, which will significantly increase the value of in vitro studies to design and run clinical DDI studies safely and effectively.

Digoxin use in patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm remains controversial. We aimed to assess the prognostic impact of digoxin in patients in sinus rhythm submitted to cardiac resynchronization therapy (CRT).Retrospective study including 297 consecutive patients in sinus rhythm, with advanced HFrEF submitted to CRT. Patients were divided into two groups - with digoxin (DG) and without digoxin (NDG). During a mean follow-up of 4.9 ± 3.4 years we evaluated the impact of digoxin on the composite endpoint defined as cardiovascular hospitalization, progression to heart transplantation and all-cause mortality.Previous to CRT, 104 patients (35%) were chronically under digoxin and 193 patients (65%) without digoxin treatment. The 2 groups did not differ significantly regarding HF functional class, HF aetiology, QRS and baseline left ventricular ejection fraction (LVEF). The proportion of responders to CRT was similar in both groups (54% in DG vs 56% in NDG, p=0.78). During the long term follow up period, the primary endpoint occurred in a higher proportion in DG patients (67 vs 48%, p=0.002). After adjustment for potential confounders, digoxin use remained as an independent predictor of the composite endpoint of CV hospitalization, heart transplantation and all-cause mortality (HR = 1.58, CI 95 [1.01 - 2.46], p = 0.045).In conclusion, in patients in sinus rhythm with HFrEF submitted to CRT, digoxin use was associated to CV hospitalization, progression to heart transplant and all-cause mortality.

Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT: We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.

Background: The pharmacodynamic effects of digoxin are susceptible to multiple factors, most notably, heart uptake of the digoxin dose and its concentration in the serum. Another important factor to mention is the renal function state of an individual. Objective: In this study, we aimed to develop a simple algorithm based on subsets of clinically relevant information, which will help to personalize digoxin based on pharmacokinetic (PK) approach which can help in marketing the appropriate utilization of this medication. Methods: This was a retrospective chart review and analysis of 48 patients who were admitted to the Drug and Poison Information center in Buraidah, Saudi Arabia, between January 2016 and April 2019. All pharmacokinetic parameters were added according to the C-peaks and C-troughs. MONOLiX® was used for data pharmacokinetic analysis. Results: Twenty-seven (56%) were males and twenty-one (44%) were females with an average age of 63.6 years across both genders. The mean volume of distribution was 496.6 litres with an average clearance of 6.6 L/h. For females, their average volume of distribution was slightly higher than that for males (526 litres compared to 473 litres). In addition, the clearance rate between both genders showed a 2.1 litre/hour discrepancy (7.8 L/h for females compared to 5.7 L/h for males). Conclusion: In order to individualize the digoxin dosage regimens, this model can be used to predict digoxin serum concentration. Further studies are needed to clarify the effects of nutritional status and co-administration of medications on digoxin pharmacokinetics.

Background:Prognosis of fetuses with hydrops and tachyarrhythmia has been portrayed as poor in most published reports. This might lead to biased counselling, unnecessary caesarean section, preterm delivery, and even termination of pregnancy.Aims:To evaluate contemporary fetal and postnatal outcomes of hydropic fetuses with fetal tachyarrhythmia when it is treated effectively and monitored systematically.Methods:This is a retrospective review of a single centre experience at the University Hospital of Wales over a 20-year period. All fetuses received high doses of flecainide and digoxin combination treatment. Tachycardia response rate, time to arrhythmia and hydrops resolution, fetal and postnatal morbidity, and mortality rates were analysed.Results:Twenty fetuses were diagnosed with hydrops fetalis and received treatment. The mechanism of fetal tachyarrhythmia was supraventricular tachycardia in thirteen and atrial flutter in eight cases. Among the 20 fetuses treated, the overall tachycardia response rate was 90% (18/20) with the restoration of sinus rhythm in 85% (17/20) of the cases. The median time to restore sinus rhythm or to rate control of the arrhythmia was 1.5 days (range 12 hours to 13 days). Hydrops resolved in 17 of the 20 fetuses, with a median time of 12 days (range 3–21 days). Four fetuses went into spontaneous preterm birth and one fetus was delivered early due to worsening hydrops. No significant neurological morbidity was observed in surviving neonates and infants on clinical examination. There was one postnatal death due to respiratory complications of prematurity in the non-responsive supraventricular tachycardia case.Conclusions:High-dose flecainide and digoxin combination offers effective treatment strategy in fetuses with hydrops and tachyarrhythmia with favourable outcomes. This study may guide more realistic counselling for pregnancies complicated by tachyarrhythmia and hydrops.

Our aim was to determine the impact of potentially inappropriate prescriptions (PIP), according to “Screening Tool of Older Persons’ Prescriptions” criteria version 2 (STOPP-2), on mortality and hospital admissions. Monocentric retrospective cohort study. Patients over 65 years of age and who were consecutively discharged from internal medicine at a Spanish university hospital in 2016 were included. The mortality and hospital admissions of the cohort of patients were analysed using their electronic health records within two years from the time of discharge. Analysis was done based on the type and number of STOPP-2 criteria as well as taking into account the total number of medications. The subdistribution hazard ratios (SHR) were estimated through a competing proportional hazards model. A total of 270 patients with a median age of 82 years (interquartile range/IQR 76–86 years), and 152 (56.3%) women were studied. It was found out that 28.3% of patients with PIP died compared to 17.2% of patients without it. Digoxin (B1 STOPP-2 criterion) with a subdistribution hazard ratio (SHR) 2.40 (95% CI 0.63–9.18), selective serotonin re-uptake inhibitors/SSRIs (D4) with a SHR 1.76 (95% CI 0.52–5.96) and neuroleptic drugs (K2) with a SHR 2.01 (95% CI 0.82–4.95) non-significantly increased the risk of death. Dementia (SHR 5.45; 95% CI 2.76–10.78) was then the only statistically significant risk factor for death. Sixty percent of patients with a PIP had shown at least one hospital admission compared to 51% of patients without it. The number of drugs at discharge (SHR 1.03; 95% CI 1.01–1.05) and having 1–2 STOPP-2 criteria (SHR 1.17; 95% CI 1.02–1.35) significantly increased the risk of hospital admission. The number of drugs at discharge and having any STOPP criteria significantly increased the risk of hospital admission in this cohort. PIP, only according to some specific STOPP-2 criteria involving digoxin, neuroleptics and SSRIs, might associate with a statistically non-significantly higher risk on mortality.

Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. Clinicaltrials.gov NCT04231435 on January 18, 2020.

Anthracyclines have cardiotoxic side effects. Cardioprotective drugs such as angiotensin-converting enzyme inhibitors and beta-blockers are therefore recommended for patients with anthracycline-induced cardiomyopathy. We herein present a 54-year-old woman with recurrent metastatic breast cancer who developed heart failure (HF) with a left ventricular ejection fraction (LVEF) of 22% after undergoing epirubicin chemotherapy. However, her HF symptoms and low LVEF persisted despite 5 months of cardioprotective therapy and additional oral pimobendan. Pimobendan was discontinued because of ventricular arrhythmia and hypotension. After the start of low-dose (0.125 mg daily) digoxin, her LVEF increased to 42%, and her HF symptoms improved with no adverse events.

Patients who present with atrial fibrillation (AF) or flutter with rapid ventricular response (RVR) and hemodynamic stability may be managed with either an intravenous (IV) nondihydropyridine calcium channel blocker (CCB) or a beta-blocker (BB). Patients without improved heart rates may need to switch to, or add, a second AV nodal blocker.To evaluate the incidence of rate control achievement and bradycardia in patients in AF or atrial flutter with RVR who receive both an intravenous CCB and a BB.A retrospective chart review of patients who received concomitant intravenous CCB or BB for the treatment of rapid AF or atrial flutter from April 2016 through July 2018 in the emergency department. Patients were excluded if the second agent was ordered but not administered, or if they received IV amiodarone or digoxin.A total of 136 patients were included in the analysis, and of those, 46% (n = 62) of patients achieved a heart rate110 bpm without bradycardia, and 3.7% (n = 5) developed bradycardia. Age, initial heart rate, time between CCB and BB administration, addition of an oral CCB or BB administration, or administration of IV magnesium did not impact target heart rate achievement.Adding a second nodal blocker in patients who did not achieve rate control with the first agent resulted in heart rate control 46% of the time. The development of symptomatic bradycardia was uncommon.

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na

BACKGROUND: The impact of published evidence on clinical practice has been understudied in pediatric cardiology. OBJECTIVE: We sought to assess changes in prescribing behavior for angiotensin-converting enzyme inhibitor (ACEI) and digoxin at discharge after initial palliation of infants with single ventricle (SV) physiology following the publication of two large studies: The Pediatric Heart Network Infant Single Ventricle (PHN-ISV) trial showing no benefit with routine ACEI use and the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) analysis showing an association between digoxin and survival. METHODS: ICD 9–10 codes identified SV infants from the Pediatric Health Information System (1/2004 to 1/2018) and charge codes identified medications at discharge. Generalized estimating equations implementing segmented logistic regressions modelled medication use, before and after (with a 3-month washout period) the relevant publication (ACEI 7/1/2010; digoxin 4/1/2016). A subgroup analysis was performed for hypoplastic left heart syndrome (HLHS). RESULTS: ACEI use (37 centers, n=4,700) at discharge did not change over time during the pre-publication period. After publication of the PHN-ISV trial, ACEI use decreased (OR: 0.61, CI 0.44–0.84, p=0.003). Digoxin use (43 centers, n=4,778) decreased by 1% monthly before publication. After the NPC-QIC publication, digoxin use increased (OR: 2.07, CI 1.05–4.08, p=0.04) with an ongoing increase of 9% per month. Results were similar for the HLHS subgroup. CONCLUSIONS: Prescribing behavior changed congruently after publication of evidence-based studies, with decreased ACEI use and increased digoxin use at discharge following initial palliation of SV infants. Our findings suggest scientific findings were rapidly implemented into clinical practice.

We present novel OCT findings of presumed acute digoxin photoreceptor toxicity in the setting of concurrent amiodarone use. Discontinuation of medications resulted in symptom abatement, vision improvement, and reversal of OCT findings.

There are limited data from randomized controlled trials comparing rate control agents in atrial fibrillation. Patient-level data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was used to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline. The rate control agents used were beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin. The independent variable for this analysis was the initial study drug used and the dependent variables were time to first hospitalization and time to death from any cause. We analyzed 1,144 out of 2,027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. There were 485 (42.5%) participants in the beta-blocker group, 344 (30%) in the calcium channel blocker group, and 315 (27.5%) in the digoxin group. All hospitalization and all-cause mortality occurred in 55.9% and 12.5% of those in the beta-blocker group, 58.4% and 16.7% in the calcium channel blocker group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group. In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with atrial fibrillation.

Despite wide usage of digoxin for various diseases in cardiology practice, its benefit is controversial and moreover it had been associated with unfavorable outcomes in some previous studies. The aim of this present study was to demonstrate whether digoxin usage was related with worse outcomes or not in patients with acute pulmonary embolisms. A total number of 1215 patients retrospectively enrolled for the study. Basic demographic features, pulmonary embolism severity index (PESI) scores, laboratory parameters and medications of patients who had been diagnosed with acute pulmonary embolism were recorded. Short (30 days) and long-term mortality were reported as the clinical outcomes. Total mortality was 15.4% in the study population and 78 of these subjects died within the first 30 days. The frequency of digoxin treatment was 8% and most of these patients were prior users. According to the binary logistic regression analyses the PESI score, right ventricle (RV) diastolic diameter, systolic pulmonary arterial pressure (sPAP), brain natriuretic peptide (BNP), troponin and digoxin therapy (odds ratio, OR: 2.82 95% confidence interval, CI: 1.39–8.31, P = 0.03) were found as independent predictors of short-term mortality. Beside these findings; sPAP, PESI score, RV diastolic diameter and digoxin therapy (hazard ratio, HR: 2.11 95%CI: 1.22–7.31, P = 0.03) were determined as independent predictors of long-term mortality in Cox regression analyses. In subgroup analysis, we determined significantly greater increase in short-term mortality with use of digoxin among patients who had chronic renal disease, among patients under thrombolytic therapy and under high dosage of digoxin therapy and among female patients. Digoxin has been used extensively for decades in the treatment of heart failure and arrhythmias despite some controversies over its benefit. For the first time in the literature, we have demonstrated independent association of digoxin therapy with short-term and long-term mortality in patients with acute pulmonary embolism.

Background Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized controlled trial setting. Observational studies of digoxin use in patients with atrial fibrillation have suggested a higher risk for poor outcomes. Less is known about this association in patients with heart failure and atrial fibrillation, the examination of which was the objective of the current study. Methods We conducted an observational propensity score-matched study of predischarge digoxin initiation in 1768 hospitalized patients with heart failure and atrial fibrillation in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, balanced on 56 baseline characteristics (mean age, 79 years; 55% women; 7% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated for the 884 patients initiated on digoxin compared with 884 not initiated on digoxin. Results HRs (95% CIs) for 30-day, 2-year, and 4-year all-cause mortality were 0.80 (0.55-1.18; P = .261), 0.94 (0.87-1.16; P = .936), and 1.01 (0.90-1.14; P = .729), respectively. Respective HRs (95% CIs) for heart failure readmission were 0.67 (0.49-0.92; P = .014), 0.81 (0.69-0.94; P = .005), and 0.85 (0.74-0.97; P = .022), and those for all-cause readmission were 0.78 (0.64-0.96; P = .016), 0.90 (0.81-1.00; P = .057), and 0.91 (0.83-1.01; P = .603). These associations were homogeneous between patients with left ventricular ejection fraction ≤45% vs >45%. Conclusions Among hospitalized older patients with heart failure (HFrEF and HFpEF) and atrial fibrillation, initiation of digoxin was associated with a lower risk of heart failure readmission but had no association with mortality.

Digoxin is indicated for the management of heart failure with reduced ejection fraction and atrial fibrillation. Despite stronger guideline recommendations for other pharmacologic and device therapies, digoxin retains a role in select patients unable to tolerate or refractory to standard therapies. Contemporary utilization of and costs related to digoxin in the United States of America (USA) remain uncharacterized. The objective of this study was to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017.We utilized the Medical Expenditure Panel Survey to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017. The Medical Expenditure Panel Survey is an overlapping panel survey that interviews households in the USA to ascertain their healthcare utilization and expenditures. Complex sampling procedures allow for nationally representative estimates of utilization and expenditures. We report the number of digoxin users and expenditures across key subgroups in 2-year increments from 2010 to 2017.The number of digoxin users in the USA declined by 47% from 766 users per 100,000 adults in 2010-11 to 402 users per 100,000 adults in 2016-17. While digoxin use declined among women and self-identified White adults, adults living at or below the federal poverty level and those who self-identified as Asian or Hispanic represent an increasing proportion of overall digoxin users. While nationwide digoxin expenditures declined by 26% from 2010-11 to 2012-13, they peaked at $260.3 million in 2014-15 and remained elevated at $188.7 million in 2016-17.Despite a nationwide trend towards declining use, digoxin remains prevalent amongst people of Asian and Hispanic descent in the USA. After a spike in cost in 2013, digoxin prices have yet to return to pre-spike levels. The role of digoxin in contemporary heart failure and arrhythmia management will continue to evolve as additional randomized and observational analyses become available.

Arrhythmias are common in single ventricle patients though their effect on outcomes during stage I palliation (S1P) is unclear.The authors sought to study associated risks for arrhythmia in patients undergoing S1P for single ventricle disease and evaluate the outcome of arrhythmias and their treatment strategies on survival.Retrospective patient, surgical, medication, and arrhythmia data were obtained from the NPC-QIC (National Pediatric Cardiology Quality Improvement Collaborative) database. Bivariate analysis of variables associated with arrhythmias, as well as those associated with survival, was performed at the time of stage II palliation. Appropriate variables were included in multivariate modeling.Of the 2,048 patients included in the study, 36% had arrhythmia noted during their S1P hospitalization, with supraventricular tachycardia (12%) and focal atrial tachycardia (11%) the most common. At S1P discharge, 11% of patients were on an antiarrhythmic medication. Arrhythmias were associated with lower survival and increased hospital length of stay. Heterotaxy syndrome, younger age at S1P, male sex, and additional anomalies were associated with increased risk of arrhythmia in multivariable modeling (P ≤ 0.01). Arrhythmia and female sex were associated with increased mortality, whereas antiarrhythmic medication and digoxin use were associated with decreased mortality (P ≤ 0.003, model area under the curve = 0.79). The use of antiarrhythmic medications within the subcohort of arrhythmia patients was also associated with decreased risk of mortality (P lt; 0.0001; odds ratio: 2.0-7.2).Arrhythmias are common during admission for S1P and associated with poor outcomes. The use of antiarrhythmic medications may improve survival, though future studies are needed.

Fetal supraventricular tachycardia management is challenging, with consequences for both the fetus and the mother. If left untreated, fetal hydrops may ensue, at which point delivery and treatment of the arrhythmia is preferred. However, if the fetus is not at term nor near-term, significant doses of antiarrhythmics may be needed to achieve adequate transplacental bioavailability. Although digoxin has classically been the mainstay of treatment, the use of flecainide or sotalol as monotherapy or in combination with digoxin is being studied. Interdisciplinary team management and shared decision-making between the physician and patient are key to achieving successful outcomes. Adult cardiologists, particularly inpatient consultation services or through burgeoning cardio-obstetrics programs, may, in some practice settings, be asked to evaluate or co-manage pregnant women with fetal arrhythmia.

Digoxin affects several cellular pathways involved in tumorigenesis. We sought to determine the association between digoxin use and pancreatic cancer risk and survival. A nested case–control study using The Health Improvement Network (THIN), a population-representative database from the United Kingdom (UK). Cases included all individuals with incident diagnosis of pancreatic cancer. Each case was matched to up to four controls using incidence density sampling based on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was digoxin therapy before cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between digoxin use and pancreatic cancer risk were estimated using conditional logistic regression. We further conducted a retrospective cohort study among pancreatic cancer cases using Cox regression model in order to evaluate the association between digoxin use and overall survival. We identified 4,113 cases with incident pancreatic cancer and 16,072 matched controls. The adjusted OR for diagnosis of pancreatic cancer among active digoxin users was 1.41 (95% CI 1.16–1.72). The risk did not change among active users with duration of therapy of more than 1 year (adjusted OR of 1.39, 95% CI 1.11–1.76). Digoxin was not associated with change in overall survival with an adjusted hazard ratio of 0.97 (95% CI 0.81–1.18). Digoxin use was associated with modestly increased pancreatic cancer risk but did not affect overall survival.

The candlenut is a highly accessible seed marketed as a natural weight-loss supplement. However, there is little known about the exact mechanism of action for weight loss nor for the many adverse symptoms it causes, such as nausea, vomiting, fatigue, cardiac dysrhythmias, and even death. In this case report, the authors present a 44-year-old woman who developed a second-degree, Mobitz type II atrioventricular block after consumption of a candlenut supplement. She presented to the emergency department with syncope and her cardiac rhythm indicated a second-degree heart block soon after ingesting candlenuts recommended by her treating physician. Interestingly, a detectable digoxin concentration obtained on hospital day 2 was measured but of unclear significance given no obvious exposure to a cardioactive glycoside. The patient's rhythm normalized on hospital day 2 and she was discharged uneventfully.

Background Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. Methods In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. Results Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. Conclusion Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

To present the crucial role of echocardiographic examination in perinatal care and analyze influence of prenatal treatment for neonatal outcome. Furthermore, the attempt to answer the question if there was any relationship between the occurrence of fetal Ebstein's anomaly and environmental risk factors in polish population.Forty-five prenatal diagnoses of Ebstein's anomaly were compiled over the 21-year period (1998‒2018) form our single unit. The analysis included the assessment of maternal parameters (age, past obstetric history, and place of residence) and fetal parameters (sex, gestational age, anatomy, the fetal cardiovascular condition assessed by the CVPS, associated extracardiac anomalies or malformations, prenatal treatment, delivery and follow-up).The average age of gravida was 29.5 years (± 5.2 years) and gravidae35 years of age accounted for 80% . There were 43 singleton pregnancies and 2 cases of multiple pregnancy. Ebstein's anomaly was mostly (averagely) diagnosed at 28th week of gestation. Forty-three fetuses had normal karyotypes and two had trisomy 21. Cardiomegaly was present in 91% (41) of fetuses. The average heart area to chest area ratio was 0.56 (± 0.12). In 21 cases, there was only fetal monitoring - echocardiographic examinations and postnatal mortality was 44.4%. In 5 cases, transplacental digoxin treatment was administered and mortality was: 40%. In another 5 cases, only steroid therapy was applied and postnatal mortality was 100%. Steroids and transplacental digoxin treatment were administered in 11 cases and mortality was 63.6%. In 3 last cases transplacental digoxin treatment, steroids and maternal hyperoxygenation therapy were given and mortality was 0%. Cesarean section rate was 49%. Moreover, due to Ebstein's anomaly regional peak of occurrence benzopyrene was deliberated as environmental risk factor.Fetal Ebstein's anomaly occurred in our population in healthy young women, expecting their first child and malformation was not related to fetus gender, nor to maternal health condition. Our data can be a new signal for the development of novel treatment strategies in therapy in fetuses with Ebstein's anomaly.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P‐glycoprotein (P‐gp). Herein, 2 open‐label, single‐sequence, crossover studies evaluated the drug‐drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P‐gp. Thirty‐two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P‐gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates’ pharmacokinetics. No drug‐drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration–time curve from time zero to the last measurable time point (AUClast) of midazolam, whereas AUClast values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite‐to‐parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19‐mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUClast. These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19‐mediated metabolism or P‐gp transport.

The blood-brain barrier (BBB) is a highly selective membrane composed predominantly of brain capillary endothelial cells expressing drug efflux transporters that prevent substrates from accessing the brain. Inflammation is associated with central nervous system diseases and can impair BBB permeability via several mechanisms, including altered transporter and cell junction expression. This can modify the brain's exposure to drugs. However, comprehensive genomic analysis of the impact of interleukin (IL)-6, which plays a key role in the inflammatory response, on the BBB is lacking. In the present study, we analyzed the effects of exposure of hCMEC/D3 cells to 20 ng/mL IL-6 for 72 h. We performed RNA sequencing and ABC transporter efflux assays. Physiologically based pharmacokinetics (PBPK) simulations were conducted to evaluate the potential impact of IL-6 on the digoxin pharmacokinetics profile and brain exposure by decreasing BBB ABCB1 efflux activity. Exposure of hCMEC/D3 cells to IL-6 triggered the deregulation of numerous genes involved in barrier permeability, such as cell junctions, focal adherens complex, and cell adhesion molecules. We observed mild modification of the mRNA expression and efflux activities of ABC transporters. PBPK simulation showed that, if we only consider the impact of IL-6 on ABCB1 transporter, the modification of the digoxin pharmacokinetics profile and brain exposure is slight. IL-6 slightly affected the gene expression levels and activities of ABC transporters on BBB cells, exhibiting a weaker effect than on hepatic cells. However, inflammation may cause other modifications, such as altered BBB permeability, that could modify drug pharmacokinetics.

Elagolix is an oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of endometriosis‐associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late‐stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug‐drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter‐mediated DDIs, elagolix area under the curve (AUC) increased by ∼2‐fold following coadministration with ketoconazole and by ∼5‐ and ∼2‐fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%‐59%) and increased digoxin AUC by 32% (23%‐41%). Elagolix decreased rosuvastatin AUC by 40% (29%‐50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150‐mg once‐daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200‐mg twice‐daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P‐glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.

Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on venetoclax disposition and P-gp inhibition by venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic venetoclax doses and to explore various clinical dosing strategies that maintain venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that venetoclax dose reductions of at least 75% are needed when venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.

Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (Papp= 10.7 ± 3.7 × 10-6 and 6.0 ± 3.4 × 10-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

This study examined the association between digoxin use and subsequent psoriasis risk using a population-based database in Taiwan. This cohort study enrolled 15 545 digoxin users and 15 545 propensity score-matched non-users from the Taiwan National Health Insurance Research Database. Each patient was independently followed up for 5 years to confirm whether they had been diagnosed with psoriasis. Cox proportional hazard regression was used to estimate psoriasis risk among digoxin users. Subgroup and sensitivity analyses were also performed. The psoriasis incidence rates were 3.02 and 2.27 per 1000 person-years among digoxin users and non-users, respectively. After adjustment for confounders, psoriasis risk was significantly higher among digoxin users than among non-users. Notably, in most subgroup analyses, digoxin use tended to increase psoriasis risk, particularly among patients with heart failure, diabetes, hypertension and hyperlipidaemia. Moreover, significantly increased psoriasis risk was noted over 2, 3, 4 and 5 years of digoxin use. In conclusion, our findings confirm that digoxin use increases subsequent psoriasis risk. Thus, physicians should be aware of this association and accordingly estimate the risks and benefits of digoxin use. Nevertheless, some patient variables, such as body mass index and obesity, were unavailable in this study. The findings in this study should be elucidated carefully because the potential effects of these factors could not be considered.

Combination use of digoxin and other medications might lead to worse outcomes in patients with atrial fibrillation (AF). We sought to investigate whether digoxin-amiodarone combination would lead to worse outcome than digoxin alone in patients with AF. Adult patients with AF and received digoxin treatment from random samples of 1,000,000 individuals covered by the National Health Insurance in Taiwan were included. Baseline characteristics including risk factors and medications were matched by propensity score (PS) in those with and without addition of amiodarone treatment. A total of 5,040 AF patients taking digoxin therapy was included. PS matching identified 1,473 patients receiving digoxin-amiodarone combination and 2,660 patients receiving digoxin with a median follow-up of 1,331 days. Digoxin-amiodarone combination was associated with increased all-cause mortality (adjusted hazard ratio (HR): 1.640, 95% confidence interval (CI): 1.470–1.829, P

Background Many patients receiving dabigatran treatment might also require bisoprolol therapy. However, there is a possibility that bisoprolol as significant P-glycoprotein inhibitor might interact with dabigatran. Study question To investigate the impact of concomitant bisoprolol therapy on dabigatran plasma level in patients with nonvalvular atrial fibrillation. Study design A pilot drug interaction study in 29 patients with nonvalvular atrial fibrillation on dabigatran therapy. Bisoprolol was administrated in 18 patients. Blood samples were collected at baseline (in the morning, before any medication was administered) and at hour 2 (2 hours after administration of dabigatran and bisoprolol). Results The dabigatran plasma level was significantly higher at baseline and at hour 2 in patients treated with bisoprolol compared with patients without bisoprolol therapy. In addition, we have shown that this increase is affected by dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin. The impact of bisoprolol on dabigatran concentration was still significant despite these confounders. Conclusions This study demonstrated the interaction between dabigatran and bisoprolol, which is modulated with dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin.

Aims The aim of this study was to investigate the impact of digoxin use on the outcomes of patients with heart failure with reduced ejection fraction (HFrEF) and its possible interaction with atrial fibrillation or use of currently guideline‐recommended treatments in the real world in China. Methods and results Patients hospitalized with HFrEF from 45 hospitals participating in the China National Heart Failure Registration Study (CN‐HF) were enrolled to assess the all‐cause mortality, HF mortality, all‐cause re‐hospitalization, and HF re‐hospitalization associated with digoxin use. Eight hundred eighty‐two eligible HFrEF patients in the CN‐HF registry were included: 372 patients with digoxin and 510 patients without digoxin. Among them, 794 (90.0%) patients were followed up for the endpoint events, with a median follow‐up of 28.6 months. Kaplan–Meier survival analysis showed that the all‐cause mortality (P < 0.001) and all‐cause re‐hospitalization (P = 0.020) were significantly higher in digoxin group than non‐digoxin group, while HF mortality (P = 0.232) and HF re‐hospitalization (P = 0.098) were similar between the two groups. The adjusted Cox proportional‐hazards regression analysis demonstrated that digoxin use remained as an independent risk factor for increased all‐cause mortality [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.27–2.44; P = 0.001] and all‐cause re‐hospitalization (HR 1.27; 95% CI 1.03–1.57; P = 0.029) in HFrEF patients and the predictive value of digoxin for all‐cause mortality irrespective of rhythm or in combination with other guideline‐recommended therapies. Conclusions Digoxin use is independently associated with increased risk of all‐cause mortality and all‐cause re‐hospitalization in HFrEF patients.

Aim: The dose of digoxin is often difficult to be determined precisely. The aim of this study was to retrospectively investigate the effect of blood biochemical indexes on the serum concentration of digoxin. Materials & methods: We collected the data of hospitalized patients treated orally with digoxin in Nanjing Drum Tower Hospital (Nanjing, China) from 2016 to 2018. Descriptive statistics was used to analyze the patients’ comprehensive condition. Results: A total of 425 patients were included in the study. Through analysis, nine factors were included in the regression model of the serum concentration of digoxin, and this regression model showed good predictive performance (r2 = 0.83138; p

New-onset of atrial fibrillation (NOAF) in critically ill patients is the most common acute cardiac dysrhythmia, but evidence-based data regarding treatment strategies are scarce. In this retrospective monocentric study, we compared effectiveness of amiodarone versus digitalis for heart rate control in critically ill patients with new-onset of atrial fibrillation. We identified a total of 209 patients for the main analysis. Amiodarone as compared to digitalis was associated with a clinically relevant faster time to heart rate control

(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na+/K+-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.

To explore the impact of digoxin on hemodynamic parameters in patients with sepsis and tachycardia admitted to the intensive care unit.Retrospective review of adult patients admitted to the medical and mixed ICU at Mayo Clinic Rochester, Minnesota from March 2008 to February 2018, initiated on digoxin within 24 h of ICU stay. Hemodynamic parameters were reviewed before digoxin administration and at 6, 12 and 24 h after. Adverse events including new onset conduction abnormalities or arrhythmias during the first 48 h after digoxin administration were reviewed by a critical care cardiologist.Study included 180 patients. We observed significant decrease in heart rate from 124 (115-138) beats/min 1 h before digoxin to 101 (87-117) 6 h after digoxin and 94 (84-112) 12 h after (p .01). Median systolic blood pressure increased from 100 (91-112) mm Hg 1 h before to 110 (100-122) (p .01) and 111 (103-124) at 6 and 12 h respectively after digoxin.Early digoxin administration in patients with sepsis and tachycardia is uncommon but associated with improvements of hemodynamic parameters. These preliminary results will help formulate future hypotheses for focused trials on utility, efficacy and safety of digoxin in sepsis.

Background Given its narrow therapeutic range, digoxin’s pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age, especially for critically ill newborns. There is limited evidence to support the safety and dosage requirements of digoxin, let alone to predict its concentrations in infants. This study aimed to compare the concentrations of digoxin predicted by traditional regression modeling and artificial neural network (ANN) modeling for newborn infants given digoxin for clinically significant patent ductus arteriosus (PDA). Methods A retrospective chart review was conducted to obtain data on digoxin use for clinically significant PDA in a neonatal intensive care unit. Newborn infants who were given digoxin and had digoxin concentration(s) within the acceptable range were identified as subjects in the training model and validation datasets, accordingly. Their demographics, disease, and medication information, which were potentially associated with heart failure, were used for model training and analysis of digoxin concentration prediction. The models were generated using backward standard multivariable linear regressions (MLRs) and a standard backpropagation algorithm of ANN, respectively. The common goodness-of-fit estimates, receiver operating characteristic curves, and classification of sensitivity and specificity of the toxic concentrations in the validation dataset obtained from MLR or ANN models were compared to identify the final better predictive model. Results Given the weakness of correlations between actual observed digoxin concentrations and pre-specified variables in newborn infants, the performance of all ANN models was better than that of MLR models for digoxin concentration prediction. In particular, the nine-parameter ANN model has better forecasting accuracy and differentiation ability for toxic concentrations. Conclusion The nine-parameter ANN model is the best alternative than the other models to predict serum digoxin concentrations whenever therapeutic drug monitoring is not available. Further cross-validations using diverse samples from different hospitals for newborn infants are needed.