RESUMEN

Futibatinib, an inhibitor of fibroblast growth factor receptor 1-4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug-drug interaction study, the effects of futibatinib on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates, and of P-gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18-55 years. In part 1, 20 participants received digoxin (P-gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10-day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3-day washout, quinidine (P-gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment-emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P-gp or BCRP substrates and that the effect of P-gp inhibition on futibatinib PK is not clinically relevant.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Digoxina , Interacciones Farmacológicas , Proteínas de Neoplasias , Rosuvastatina Cálcica , Humanos , Adulto , Masculino , Femenino , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Persona de Mediana Edad , Adulto Joven , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Adolescente , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Digoxina/farmacocinética , Digoxina/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Voluntarios Sanos , Área Bajo la Curva , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo

RESUMEN

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.

Asunto(s)

Esclerosis Amiotrófica Lateral , Encéfalo , Cafeína , Modelos Animales de Enfermedad , Ratones Transgénicos , Médula Espinal , Animales , Cafeína/administración & dosificación , Cafeína/farmacocinética , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Masculino , Femenino , Ratones , Administración Oral , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Digoxina/farmacocinética , Digoxina/administración & dosificación , Sulfasalazina/farmacocinética , Sulfasalazina/administración & dosificación , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología

RESUMEN

Digoxin, the oldest known cardiovascular drug, is still used today to treat heart failure and atrial fibrillation. Because it has a narrow therapeutic index and multiple interactions, it frequently causes toxicity with a wide range of symptoms and cardiac arrhythmias. More importantly, elevated serum digoxin levels have been linked to a higher risk of death in patients with heart failure or atrial fibrillation, even without signs or symptoms of toxicity. This article reviews the current state of digoxin use, its pharmacologic principles, and the mechanisms, clinical presentation, and management of toxicity.

Asunto(s)

Fibrilación Atrial , Digoxina , Insuficiencia Cardíaca , Digoxina/efectos adversos , Digoxina/sangre , Humanos , Fibrilación Atrial/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamente , Cardiotónicos/uso terapéutico , Cardiotónicos/efectos adversos , Cardiotónicos/farmacología , Antiarrítmicos/efectos adversos

RESUMEN

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance transporter 2 (MRP2) are efflux transporters involved in the absorption, excretion, and distribution of drugs. Bidirectional cell assays are recognized models for evaluating the potential of new drugs as substrates or inhibitors of efflux transporters. However, the assays are complicated by a lack of selective substrates and/or inhibitors, as well simultaneous expression of several efflux transporters in cell lines used in efflux models. This project aims to evaluate an in vitro efflux cell assay employing model substrates and inhibitors of P-gp, BCRP and MRP2 with knockout (KO) cell lines. The efflux ratios (ER) of P-gp (digoxin, paclitaxel), BCRP (prazosin, rosuvastatin), MRP2 (etoposide, olmesartan) and mixed (methotrexate, mitoxantrone) substrates were determined in wild-type C2BBe1 and KO cells. For digoxin and paclitaxel, the ER decreased to less than 2 in the cell lines lacking P-gp expression. The ER decreased to less than 3 for prazosin and less than 2 for rosuvastatin in the cell lines lacking BCRP expression. For etoposide and olmesartan, the ER decreased to less than 2 in the cell lines lacking MRP2 expression. The ER of methotrexate and mitoxantrone decreased in single- and double-KO cells without BCRP and MRP2 expression. These results show that KO cell lines have the potential to better interpret complex drug-transporter interactions without depending upon multi-targeted inhibitors or overlapping substrates. For drugs that are substrates of multiple transporters, the single- and double-KO cells may be used to assess their affinities for the different transporters.

Asunto(s)

Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas de Neoplasias , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Técnicas de Inactivación de Genes , Transporte Biológico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Línea Celular , Digoxina/farmacología , Digoxina/farmacocinética , Digoxina/metabolismo , Prazosina/farmacología , Paclitaxel/farmacología , Animales

RESUMEN

Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so-called redifferentiation, are promising but not suitable for all patients. Preclinical studies, in human cell lines just as in a murine model, have shown that the cardiac glycoside digoxin restored RAI uptake. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI-refractory NMTC. Methods: Eight patients with metastasized RAI-refractory NMTC were included between November 2022 and June 2023. Before treatment, a baseline [123I]NaI scintigraphy was performed. Thereafter, patients were treated with digoxin for 3 weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After 1 week, the digoxin plasma concentration was measured, and the digoxin dose was adjusted if necessary. After 3 weeks of digoxin treatment, a second [123I]NaI scintigraphy was performed. RAI uptake was compared between the two scintigraphies. Results: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. Conclusion: Contrary to results from preclinical trials, in this trial, 3 weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach toward optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

Asunto(s)

Digoxina , Radioisótopos de Yodo , Neoplasias de la Tiroides , Humanos , Digoxina/uso terapéutico , Digoxina/farmacocinética , Digoxina/farmacología , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/patología , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Adulto , Cintigrafía

RESUMEN

BACKGROUND: Intravenous digoxin is still used in emergency departments (EDs) to treat patients with acute heart failure (AHF), especially in those with rapid atrial fibrillation. Nonetheless, many emergency physicians are reluctant to use intravenous digoxin in patients with advanced age, impaired renal function, and potassium disturbances due to its potential capacity to increase adverse outcomes. OBJECTIVE: We investigated whether intravenous digoxin used to treat rapid atrial fibrillation in patients with AHF may influence mortality in patients with specific age, estimated glomerular filtration rate (eGFR), and serum potassium classes. DESIGN: A secondary analysis of patients included in in the Spanish EAHFE cohort, which includes patients diagnosed with AHF in the ED. SETTING: 45 Spanish EDs. PARTICIPANTS: Two thousand one hundred ninety-four patients with AHF and rapid atrial fibrillation (heart rate ≥100 bpm) not receiving digoxin at home, divided according to whether they were or were not treated with intravenous digoxin in the ED. OUTCOME: The relationships between age, eGFR, and potassium with 30-day mortality were investigated using restricted cubic spline (RCS) models adjusted for relevant patient and episode variables. The impact of digoxin use on such relationships was assessed by checking interaction. MAIN RESULTS: The median age of the patients was 82 years [interquartile range (IQR) = 76-87], 61.4% were women, 65.2% had previous episodes of atrial fibrillation, and the median heart rate at ED arrival was 120 bpm (IQR = 109-135). Digoxin and no digoxin groups were formed by 864 (39.4%) and 1330 (60.6%) patients, respectively. There were 191 deaths within the 30-day follow-up period (8.9%), with no differences between patients receiving or not receiving digoxin (8.5 vs. 9.1%, P  = 0.636). Although analysis of RCS curves showed that death was associated with advanced age, worse renal function, and hypo- and hyperkalemia, use of intravenous digoxin did not interact with any of these relationships ( P  = 0.156 for age, P  = 0.156 for eGFR; P  = 0.429 for potassium). CONCLUSION: The use of intravenous digoxin in the ED was not associated with significant changes in 30-day mortality, which was confirmed irrespective of patient age or the existence of renal dysfunction or serum potassium disturbances.

Asunto(s)

Fibrilación Atrial , Digoxina , Tasa de Filtración Glomerular , Insuficiencia Cardíaca , Potasio , Humanos , Digoxina/administración & dosificación , Digoxina/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/mortalidad , Femenino , Masculino , Anciano , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Potasio/sangre , Potasio/administración & dosificación , Anciano de 80 o más Años , Factores de Edad , Servicio de Urgencia en Hospital , Administración Intravenosa , Antiarrítmicos/administración & dosificación , Antiarrítmicos/uso terapéutico , España , Enfermedad Aguda , Infusiones Intravenosas

RESUMEN

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Asunto(s)

Digoxina , Neoplasias Endometriales , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Digoxina/farmacología , Digoxina/uso terapéutico , Humanos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Animales , Línea Celular Tumoral , Ratones , Esferoides Celulares/efectos de los fármacos , Reposicionamiento de Medicamentos , Digitoxina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento

RESUMEN

Consumer-grade wearable technology has the potential to support clinical research and patient management. Here, we report results from the RATE-AF trial wearables study, which was designed to compare heart rate in older, multimorbid patients with permanent atrial fibrillation and heart failure who were randomized to treatment with either digoxin or beta-blockers. Heart rate (n = 143,379,796) and physical activity (n = 23,704,307) intervals were obtained from 53 participants (mean age 75.6 years (s.d. 8.4), 40% women) using a wrist-worn wearable linked to a smartphone for 20 weeks. Heart rates in participants treated with digoxin versus beta-blockers were not significantly different (regression coefficient 1.22 (95% confidence interval (CI) -2.82 to 5.27; P = 0.55); adjusted 0.66 (95% CI -3.45 to 4.77; P = 0.75)). No difference in heart rate was observed between the two groups of patients after accounting for physical activity (P = 0.74) or patients with high activity levels (≥30,000 steps per week; P = 0.97). Using a convolutional neural network designed to account for missing data, we found that wearable device data could predict New York Heart Association functional class 5 months after baseline assessment similarly to standard clinical measures of electrocardiographic heart rate and 6-minute walk test (F1 score 0.56 (95% CI 0.41 to 0.70) versus 0.55 (95% CI 0.41 to 0.68); P = 0.88 for comparison). The results of this study indicate that digoxin and beta-blockers have equivalent effects on heart rate in atrial fibrillation at rest and on exertion, and suggest that dynamic monitoring of individuals with arrhythmia using wearable technology could be an alternative to in-person assessment. ClinicalTrials.gov identifier: NCT02391337 .

Asunto(s)

Antagonistas Adrenérgicos beta , Fibrilación Atrial , Digoxina , Frecuencia Cardíaca , Dispositivos Electrónicos Vestibles , Humanos , Digoxina/uso terapéutico , Digoxina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Femenino , Masculino , Anciano , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/farmacología , Anciano de 80 o más Años , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Ejercicio Físico , Teléfono Inteligente

RESUMEN

AIMS: Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. METHODS: We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users. RESULTS: The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]). CONCLUSIONS: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Muerte Súbita Cardíaca , Digoxina , Genotipo , Humanos , Digoxina/efectos adversos , Digoxina/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/epidemiología , Anciano , Estudios Prospectivos , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Riesgo , Relación Dosis-Respuesta a Droga , Polimorfismo de Nucleótido Simple , Países Bajos/epidemiología , Cardiotónicos/efectos adversos , Cardiotónicos/administración & dosificación , Cardiotónicos/uso terapéutico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/inducido químicamente

RESUMEN

There are many therapeutic modalities for plantar warts, however treating it remains challenging. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide were observed to be effective and safe, however no comparison study between them was done. Our study was conducted to evaluate the efficacy of both therapies in the treatment of plantar warts. 90 adult patients with multiple recalcitrant plantar warts were included in our study. They were randomly allocated to one of three groups; combined digoxin and furosemide, 5-fluorouarcil, or normal saline group. Fortnightly injections were done into all studied warts till complete clearance or up to 5 sessions. Warts were evaluated clinically and dermoscopically. Clinical response was reported in 24 patients (80%) of the combined digoxin and furosemide group with 40% complete response and in 24 patients (80%) of the 5-fluorouarcil group with 33.3% complete response. No statistically significant difference was observed between the two groups concerning efficacy and safety. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide are nearly equivalent in efficacy and safety for plantar wart treatment. Dermoscopy helps to take the truthful judgment about complete clearance of warts.

Asunto(s)

Digoxina , Furosemida , Inyecciones Intralesiones , Verrugas , Humanos , Furosemida/administración & dosificación , Masculino , Femenino , Adulto , Verrugas/tratamiento farmacológico , Digoxina/administración & dosificación , Resultado del Tratamiento , Estudios Prospectivos , Adulto Joven , Persona de Mediana Edad , Quimioterapia Combinada/métodos , Adolescente , Dermoscopía , Flucitosina/administración & dosificación

RESUMEN

BACKGROUND: Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a potentially life-threatening clinical condition characterized by bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia. It constitutes a vicious circle in which the accumulation of pharmacologically active compounds and hyperkalemia lead to hemodynamic instability and heart failure. CASE PRESENTATION: A 66-year-old Caucasian female patient was admitted to the emergency department presenting with fatigue and bradycardia. Upon examination, the patient was found to be anuric and hypotensive. Laboratory investigations revealed metabolic acidosis and hyperkalemia. Clinical evaluation suggested signs of digoxin toxicity, with serum digoxin concentrations persistently elevated over several days. Despite the implementation of antikalemic measures, the patient's condition remained refractory, necessitating renal dialysis and administration of digoxin immune fab. CONCLUSION: Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a life-threatening condition that requires prompt management. It is important to also consider potential coexisting clinical manifestations indicative of intoxication from other pharmacological agents. Specifically, symptoms associated with the accumulation of drugs eliminated via the kidneys, such as digoxin. These manifestations may warrant targeted therapeutic measures.

Asunto(s)

Bradicardia , Digoxina , Hiperpotasemia , Diálisis Renal , Humanos , Femenino , Anciano , Digoxina/efectos adversos , Hiperpotasemia/inducido químicamente , Bradicardia/inducido químicamente , Insuficiencia Renal/inducido químicamente , Antiarrítmicos/efectos adversos , Síndrome , Acidosis/inducido químicamente , Choque/inducido químicamente , Bloqueo Atrioventricular/inducido químicamente , Fragmentos Fab de Inmunoglobulinas

Asunto(s)

Digoxina , Digoxina/uso terapéutico , Humanos , Fibrilación Atrial/tratamiento farmacológico , Antiarrítmicos/uso terapéutico , Cardiotónicos/uso terapéutico

RESUMEN

Atrial fibrillation (AF) is common, but there are limited data to guide selection of rate control medications (RCM). Reasons for selection are multivariable, and the impact on outcomes is unknown. We investigated prescribing patterns of RCM among patients with AF. Using a nationwide database, we identified 135,927 patients with AF. We stratified by baseline presence of heart failure with reduced ejection fraction (HFrEF) and examined prescription rates of RCM as a function of clinical variables. We also evaluated associations with clinical outcomes. Beta blockers (BB) were most commonly prescribed (44.6%), then calcium channel blockers (CCB) (14.0%) and digoxin (8.6%). Patients prescribed BB were more likely male (45.6% vs 43.4%, p < 0.0001), patients prescribed CCB were less likely male (12.0% vs 16.3%, p < 0.0001). There were higher rates of HF hospitalization (HFH) among females and those with Medicaid. Randomized trials are needed to define optimal choice of RCM.

Asunto(s)

Antagonistas Adrenérgicos beta , Antiarrítmicos , Fibrilación Atrial , Bloqueadores de los Canales de Calcio , Pautas de la Práctica en Medicina , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Femenino , Masculino , Anciano , Pautas de la Práctica en Medicina/estadística & datos numéricos , Antiarrítmicos/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Estados Unidos/epidemiología , Persona de Mediana Edad , Bloqueadores de los Canales de Calcio/uso terapéutico , Digoxina/uso terapéutico , Frecuencia Cardíaca/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Resultado del Tratamiento , Hospitalización/estadística & datos numéricos , Estudios Retrospectivos , Bases de Datos Factuales , Anciano de 80 o más Años , Volumen Sistólico/fisiología

RESUMEN

BACKGROUND: Some studies have shown digoxin use to be associated with adverse outcomes, including increased mortality. There are limited data on whether digoxin use is associated with increased risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in heart failure patients with an implantable cardioverter-defibrillator (ICD). OBJECTIVES: This study sought to assess whether digoxin use is associated with increased risk of VT/VF in patients with heart failure with reduced ejection fraction with a primary prevention ICD in landmark clinical trials. METHODS: The study cohort consisted of patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in 4 landmark MADIT trials (Multicenter Automatic Defibrillator Implantation Trials). We employed propensity score quintile stratification for treatment with digoxin as well as additional multivariable adjustment to assess the risk of digoxin vs no-digoxin therapy for the endpoints of first and recurrent VT/VF and all-cause mortality. The proportional hazards regression models for arrhythmia-specific endpoints incorporated adjustments for the competing risk of death. RESULTS: At baseline, 1,155 of 4,499 patients were on digoxin (26%). After propensity score quintile stratification, patients prescribed digoxin were shown to exhibit a statistically significant 48% increased risk of VT/VF (P < 0.001), 42% increased risk of the composite of VT/VF or death (P < 0.001), and a 37% increased risk of all-cause mortality (P = 0.006). Digoxin use was also associated with increased risk of appropriate ICD shocks (HR: 1.91; P < 0.001) and with increased burden of VT/VF events (HR: 1.46; P = 0.001). CONCLUSIONS: Our findings suggests that digoxin use is associated with ventricular tachyarrhythmia and death in heart failure with reduced ejection fraction patients with an ICD.

Asunto(s)

Desfibriladores Implantables , Digoxina , Insuficiencia Cardíaca , Taquicardia Ventricular , Humanos , Digoxina/uso terapéutico , Digoxina/efectos adversos , Desfibriladores Implantables/efectos adversos , Femenino , Taquicardia Ventricular/mortalidad , Masculino , Persona de Mediana Edad , Anciano , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/tratamiento farmacológico , Puntaje de Propensión , Fibrilación Ventricular/mortalidad , Antiarrítmicos/uso terapéutico , Antiarrítmicos/efectos adversos , Estudios de Cohortes , Factores de Riesgo

RESUMEN

IMPORTANCE: Trimethoprim-sulfamethoxazole (TMP-SMX) may increase digoxin concentration, a medication with a narrow therapeutic index. Small changes in digoxin concentration could predispose individuals to the risk of toxicity. OBJECTIVE: To characterize the risk of digoxin toxicity in older adults taking digoxin following co-prescription of TMP-SMX compared with co-prescription of amoxicillin. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective population-based cohort study in Ontario, Canada (2002-2020) using linked health care data. Participants comprised 47,961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74-86]) who were newly treated with TMP-SMX (n = 10,273) compared with those newly treated with amoxicillin (n = 37,688). EXPOSURE: Co-prescription of TMP-SMX versus amoxicillin in older adults concurrently taking digoxin. MAIN OUTCOME AND MEASURE: The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD. RESULTS: A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted RR, 5.71 [95% confidence interval (CI), 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]). CONCLUSION AND RELEVANCE: In older adults taking digoxin, the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co-prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Physicians should prescribe an alternative antibiotic when clinically appropriate. If TMP-SMX must be co-prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose-reduced on an individual basis.

Asunto(s)

Amoxicilina , Antibacterianos , Digoxina , Combinación Trimetoprim y Sulfametoxazol , Humanos , Digoxina/efectos adversos , Digoxina/administración & dosificación , Anciano , Femenino , Masculino , Anciano de 80 o más Años , Estudios Retrospectivos , Amoxicilina/efectos adversos , Amoxicilina/administración & dosificación , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Combinación Trimetoprim y Sulfametoxazol/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Estudios de Cohortes , Interacciones Farmacológicas , Ontario/epidemiología , Cardiotónicos/efectos adversos , Cardiotónicos/uso terapéutico , Cardiotónicos/administración & dosificación

RESUMEN

The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV) outcomes and death rates among patients with atrial fibrillation (AF) who were prescribed with beta-blockers, digoxin or combination therapy. Data from phase II/III of the prospective Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) were analysed. The risk of major cardiovascular events (MACE) and death among patients with different prescriptions using COX proportional hazard regression was considered. Propensity score (PS) matching and weighting were further used to adjust for potential confounders of prescription use. A total of 14,201 patients [median age: 71.0 (IQR 64.0-77.0) years; 46.2% female] were recruited. After a median follow-up of 3.0 (IQR 2.4-3.1) years, 864 MACE, and 988 all-cause deaths were recorded. The incidence rate (IR) of MACE was 22.4 (95%CI 21.0-24.0) per 1000 person-years, while the IR of all-cause death was 25.4 (95%CI 23.8-27.0) per 1000 person-years. After multivariate adjustment with Cox regression, the risk of MACE (HR 1.35, 95% CI 1.09-1.68) and the risk of all-cause death (HR 1.28, 95%CI 1.04-1.57) were significantly higher in the combination therapy group, compared to the beta-blockers alone group. The risks of MACE and all-cause death remained significant in both PS matched and PS weighted cohort Among AF patients, combination therapy of beta-blockers and digoxin was associated with higher risks of MACE and all-cause death compared to beta-blockers alone.

Asunto(s)

Antagonistas Adrenérgicos beta , Fibrilación Atrial , Digoxina , Quimioterapia Combinada , Sistema de Registros , Humanos , Digoxina/uso terapéutico , Femenino , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/mortalidad , Masculino , Sistema de Registros/estadística & datos numéricos , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/tratamiento farmacológico , Modelos de Riesgos Proporcionales , Puntaje de Propensión , Antiarrítmicos/uso terapéutico , Antiarrítmicos/efectos adversos

RESUMEN

BACKGROUND: Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status and the presence of electrocardiographic and electrolytic disturbances. OBJECTIVE: To identify factors associated with seven-day and thirty-day mortality in digoxin poisoning. DESIGN, SETTINGS AND PARTICIPANTS: A retrospective, observational, multicenter study was conducted across 15 Hospital Emergency Departments (HED) in Spain. All patients over 18 years of age who presented to participating HEDs from 2015 to 2021 were included. The inclusion criteria encompassed individuals meeting the criteria for digoxin poisoning, whether acute or chronic. OUTCOMES MEASURE AND ANALYSIS: To identify independent factors associated with 7-day and 30-day mortality, a multivariate analysis was conducted. This analysis included variables of clinical significance, as well as those exhibiting a trend (p < 0.1) or significance in the bivariate analysis. MAIN FINDINGS: A total of 658 cases of digoxin poisoning were identified. Mortality rates were 4.5% (30 patients) at seven days and 11.1% (73 patients) at thirty days. Regarding 7-day mortality, the mean age of deceased patients was comparable to survivors (84.7 (8.9) vs 83.9 (7.9) years; p = ns). The multivariate analysis revealed that factors independently associated with 7-day mortality encompassed the extent of dependence assessed by the Barthel Index (BI 60-89 OR 0.28; 95% CI 0.10-0.77; p = 0.014 and BI>90 OR 0.22; 95% CI 0.08-0.63; p = 0.005), the identification of ventricular arrhythmias (OR 1.34; 95% CI 1.34-25.21; p = 0.019), and the presence of circulatory (OR 2.84; 95% CI 1.19-6.27; p = 0.019) and neurological manifestations (OR 2.67; 95% CI 1.13-6.27; p = 0.025). Factors independently associated with 30-day mortality encompassed extent of dependence (BI 60-89 OR 0.37; 95% CI 0.20-0.71; p = 0.003 and BI>90 OR 0.18; 95% CI 0.09-0.39; p < 0.001) and the identification of circulatory (OR 2.13; 95% CI 1.10-4.15; p = 0.025) and neurological manifestations (OR 2.39; 95% CI 1.25-3.89; p = 0.006). CONCLUSIONS: The study identifies the degree of dependency assessed by the Barthel Index and the presence of cardiovascular and neurological symptoms as independent predictors of both 7-day and 30-day mortality. Additionally, the detection of ventricular arrhythmia is also an independent factor for 7-day mortality.

Asunto(s)

Digoxina , Humanos , Femenino , Digoxina/envenenamiento , Digoxina/sangre , Masculino , Estudios Retrospectivos , Anciano , Anciano de 80 o más Años , España/epidemiología , Servicio de Urgencia en Hospital/estadística & datos numéricos , Factores de Riesgo , Persona de Mediana Edad

RESUMEN

Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.

Asunto(s)

Digoxina , Monitoreo de Drogas , Tacrolimus , Vancomicina , Humanos , Monitoreo de Drogas/métodos , Estudios Retrospectivos , Masculino , Femenino , Tacrolimus/uso terapéutico , Tacrolimus/sangre , Vancomicina/sangre , Vancomicina/uso terapéutico , Vancomicina/farmacocinética , Persona de Mediana Edad , Anciano , Digoxina/sangre , Digoxina/uso terapéutico , Unidades de Cuidados Intensivos , Adulto , Creatinina/sangre , Nitrógeno de la Urea Sanguínea , Péptido Natriurético Encefálico/sangre

RESUMEN

Determination of digoxin through in-capillary derivatisation based on the formation of o-tolyl- and 2-naphthyl-anionic boronate esters in combination with large volume sample stacking-capillary electrophoresis is proposed. The derivatisation reaction was performed at basic pH values to obtain compounds with a charge and chromophore group during the stacking process. After stacking, the species were separated and detected at 225 nm using p-nitrophenol as an internal standard. Stacking and derivatisation parameters such as pre-concentration time, preconcentration voltage and injection time (relation between the analyte and the derivatisation agent) were evaluated using a Box-Behnken design. Under optimal conditions, the proposed method exhibits a linear range of 1.08-50.00 µM with a limit of detection of 0.36 µM; additionally, adequate repeatability and reproducibility was obtained (%RSD ≤ 5.0%). The methodology was validated by comparing it to an HPLC-UV established methodology and was successfully applied for the determination of digoxin in pharmaceutical tablets and blood serum samples, showing a positive performance for these matrices.

Asunto(s)

Ácidos Borónicos , Digoxina , Electroforesis Capilar , Digoxina/sangre , Digoxina/análisis , Digoxina/química , Electroforesis Capilar/métodos , Ácidos Borónicos/química , Humanos , Ésteres/química , Límite de Detección , Reproducibilidad de los Resultados , Comprimidos

RESUMEN

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.

Asunto(s)

Humor Acuoso , Digoxina , Presión Intraocular , Macaca fascicularis , Hipertensión Ocular , Animales , Presión Intraocular/efectos de los fármacos , Digoxina/farmacología , Humor Acuoso/metabolismo , Humor Acuoso/efectos de los fármacos , Hipertensión Ocular/tratamiento farmacológico , Hipertensión Ocular/fisiopatología , Hipertensión Ocular/metabolismo , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Glaucoma/metabolismo , Glaucoma/fisiopatología , Conejos , Humanos , Cuerpo Ciliar/efectos de los fármacos , Cuerpo Ciliar/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Masculino , Malla Trabecular/efectos de los fármacos , Malla Trabecular/metabolismo