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2.
S D Med ; 72(7): 310-312, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31461586

RESUMO

Intrathecal administration of digoxin occurs very rarely. Some case reports of inadvertently administering it when performing spinal/epidural anesthesia were described. We report for the first time a case of a chemical meningitis and status epilepticus caused by accidental epidural administration of digoxin. A 26-year-old female underwent epidural anesthesia for a planned cesarean section (CS). Post operatively the patient became lethargic, agitated and encephalopathic, she was intubated and transferred to our hospital intensive care unit (ICU). She had seizures on admission. Electroencephalogram (EEG) was performed and showed generalized slowing and status epilepticus with a focus noted in the right temporal region which resolved after antiepileptic medication administration. A lumbar puncture (LP) was performed; cerebro-spinal fluid (CSF) was suggestive for meningitis. However, there was no evidence for viral or bacterial infections. Within a day of admission, the referring hospital informed us that the patient received 250 mcg of digoxininadvertently-through epidural injection. The patient remained intubated for four days. She became more responsive and alert and was eventually extubated. After extubation, the patient was responsive and full neurological exam and brain imaging were normal. She was discharged from the hospital after seven days.


Assuntos
Anestesia Epidural , Digoxina/efeitos adversos , Meningite , Estado Epiléptico , Adulto , Anestesia Epidural/efeitos adversos , Cesárea , Digoxina/administração & dosagem , Feminino , Humanos , Meningite/induzido quimicamente , Gravidez , Estado Epiléptico/induzido quimicamente
3.
Monaldi Arch Chest Dis ; 89(2)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162487

RESUMO

Heart failure (HF) and atrial fibrillation (AF) often coexist. Subjects with permanent AF show the highest prevalence of HF. Patients with incident AF have HF in a great number of cases and, reciprocally, in patients with incident HF, an AF can be frequently found. The simultaneous presence of the two conditions is associated with mortality rates higher than those observed in individuals with only one or none of them. Interestingly, HF and AF could synergistically promote in elderly patients the development of disability and dementia. Inflammatory mechanisms coupled with changes of renin-angiotensin system, hormonal pathways and neuro-mediators could simultaneously promote left atrium remodeling and sustain both HF and AF. Beta-blockers and digoxin seem to have small therapeutic effect and limited influence on prognosis in these very complex patients. Sinus rhythm restoration could slow down the progression of disability in symptomatic subjects. Recent evidence seem to suggest that upstream therapy coupled with rehabilitation, and that AV node ablation associated with cardiac resynchronization therapy could benefit subjects with HF and AF. In conclusion, elderly patients simultaneously presenting problems of cardiac function and arrhythmia are an important challenge for geriatric medicine, and request important efforts to improve their functional profile and prognosis.


Assuntos
Fibrilação Atrial/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Fibrilação Atrial/terapia , Reabilitação Cardíaca/métodos , Terapia de Ressincronização Cardíaca/métodos , Digoxina/administração & dosagem , Insuficiência Cardíaca/terapia , Humanos , Prognóstico
4.
Medicine (Baltimore) ; 98(14): e15088, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946364

RESUMO

Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher trough SDC (1.20 ±â€Š0.50 ng/mL) than recommended trough SDC for heart failure patients. Trough SDC was not significantly influenced by mutations of OATP1B1 388A>G (P = .890), 521T>C (P = .054), and OATP1B3 699G>A (P = .854). Patients with OATP1B1 521T>C mutant-type carrier had slightly higher trough SDC (0.98 ±â€Š0.53 ng/mL) than those with wild-type carrier (0.74 ±â€Š0.40 ng/mL) when they have repaired renal function.Heart failure patients with severe renal dysfunction (GFR<60 mL/min) and/or OATP1B1 521T>C mutant-type carriers are recommended a smaller dosage of digoxin and strict therapeutic drug monitoring.


Assuntos
Cardiotônicos/sangue , Digoxina/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Mutação , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Idoso , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , China , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Prospectivos
5.
Emergencias (Sant Vicenç dels Horts) ; 31(2): 99-106, abr. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-182526

RESUMO

Objetivos: Estudiar las características de los pacientes que consultan por un episodio de fibrilación auricular (FA) en los servicios de urgencias hospitalarios (SUH), en función de si la FA es de novo o conocida previamente, y la reconsulta relacionada con la FA a los 30 días (R30d). Método: Estudio observacional de cohorte prospectivo y multicéntrico que incluyó a todos los pacientes $ 18 años que consultaron por síntomas relacionados con una FA o el hallazgo de una FA en 5 SUH catalanes. Se recogieron variables demográficas, del episodio agudo, de manejo en urgencias y la R30d. Resultados: De los 1.199 pacientes, 1.052 tuvieron seguimiento a 30 días. La edad media fue de 73 (DE 13) años y 646 (53,9%) eran mujeres. Seiscientos cincuenta y dos pacientes (54,4%) tenían una FA conocida, los cuales tenían mayor edad, presencia de comorbilidades y uso de antiarrítmicos y anticoagulantes orales. Hubo escasas diferencias en el manejo farmacológico en urgencias. La R30d fue de un 7,9%, y fue más frecuente cuando se usó digoxina en urgencias y bloqueadores de los canales del calcio al alta. Conclusiones: Existen diferencias basales entre los pacientes con FA de novo y conocida, pero estas son escasas en el manejo en urgencias. En pacientes atendidos por fibrilación auricular en urgencias, la R30d se relacionó con el uso de digoxina en urgencias y de bloqueadores de los canales del calcio al alta


Objectives: To study the characteristics of patients attending a hospital emergency department (ED) with de novo or previously diagnosed atrial fibrillation (AF), and to determine the rate of revisits for AF within 30 days of discharge. Methods: Prospective multicenter, observational cohort study of patients aged 18 years or older who came to 5 Catalan EDs with symptoms of AF or who were found to have AF on examination. We recorded demographic information and data related to the acute episode and ED management on the first or other visits within 30 days. Results: We had complete follow-up data for 1052 of the 1199 patients initially registered. The mean (SD) age was 73 (13) years, and 646 (53.9%) were women. AF had already been diagnosed in 652 (54.4%). Patients with diagnosed AF were older, had more concomitant conditions, and were more likely to be taking antiarrhythmic and/or anticoagulant drugs. Pharmacologic management in the ED was similar. The 30-day revisiting rate was 7.9% , and revisits were more frequent when digoxin was used in the ED and/or calcium channel blockers were prescribed on discharge. Conclusions: We detected differences between ED patients with de novo FA and previously diagnosed FA, but management of the 2 groups was similar. The 30-day revisiting rate was associated with use of digoxin in the ED and the prescription of calcium channel blockers on discharge


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Registros/estatística & dados numéricos , Fibrilação Atrial/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Digoxina/administração & dosagem , Canais de Cálcio/administração & dosagem , Readmissão do Paciente/normas , Fatores de Risco
6.
PLoS One ; 14(3): e0214407, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30908540

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in human infants. Bovine RSV infection of neonatal calves is pathologically and immunologically similar to RSV infection in infants, and is therefore a useful preclinical model for testing novel therapeutics. Treatment of severe RSV bronchiolitis relies on supportive care and may include use of bronchodilators and inhaled or systemic corticosteroids. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. It is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection. Digoxin was recently identified to selectively inhibit IL-17 production by antagonizing its transcription factor, retinoid-related orphan receptor γ t (RORγt). Digoxin inhibits RORγt binding to IL-17 and Th17 associated genes, and suppresses IL-17 production in vitro in human and murine leukocytes and in vivo in rodent models of autoimmune disease. We demonstrate here that in vitro and in vivo digoxin treatment also inhibits IL-17 production by bovine leukocytes. To determine the role of IL-17 in primary RSV infection, calves were treated prophylactically with digoxin and infected with BRSV. Digoxin treated calves demonstrated reduced signs of clinical illness after BRSV infection, and reduced lung pathology compared to untreated control calves. Digoxin treatment did not adversely affect virus shedding or lung viral burden, but had a significant impact on pulmonary inflammatory cytokine expression on day 10 post infection. Together, our results suggest that exacerbated expression of IL-17 has a negative impact on RSV disease, and that development of specific therapies targeting Th17 immunity may be a promising strategy to improve disease outcome during severe RSV infection.


Assuntos
Bronquiolite/virologia , Digoxina/administração & dosagem , Interleucina-17/metabolismo , Vírus Sincicial Respiratório Bovino/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Bovinos , Digoxina/farmacologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/virologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Profilaxia Pós-Exposição , Vírus Sincicial Respiratório Bovino/imunologia , Células Th17/imunologia , Células Th17/virologia
7.
BJOG ; 126(7): 885-889, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30703286

RESUMO

OBJECTIVE: Intra-amniotic injection of digoxin is a well-known method for feticide before inducing a termination of pregnancy (TOP) at 17-24 weeks of gestation. Information on its effectiveness when administered after 24 weeks of gestation is limited. This study evaluated the efficacy of intra-amniotic digoxin injection for inducing fetal demise within 18-24 hours, at 21-30 weeks of gestation, and its safety. DESIGN: Prospective cohort study. SETTING: Tertiary university medical centre. POPULATION: Women at 21-30 weeks of gestation with a singleton pregnancy, admitted for TOP. METHODS: Intra-amniotic injection of 2 mg of digoxin was performed 1 day before medical TOP. Fetal heart activity was evaluated by ultrasound for 18-24 hours after the injection. Serum digoxin level and maternal electrocardiogram (ECG) were evaluated 6, 10, and 20 hours after injection. MAIN OUTCOME MEASURE: Frequency of successful fetal demise. RESULTS: Fifty-nine women participated in the study. The mean gestational age was 24+2  weeks (range 21+0 -30+0 ), with 29 (49.2%) beyond 24+0  weeks of gestation. Fetal cardiac activity arrest was achieved in 55/59 cases (93.2%). Normal maternal ECG recordings were noted in all cases. Mean serum digoxin levels 6 and 10 hours after injection were in the therapeutic range (1.3 ± 0.7 ng/l and 1.24 ± 0.49 ng/l, respectively) and below the toxic level (2 ng/l). Extramural delivery following digoxin did not occur. There were no cases of chorioamnionitis. CONCLUSION: Intra-amniotic digoxin for feticide at 21-30 weeks of gestation in a singleton pregnancy appears effective and safe before TOP at advanced gestational ages. TWEETABLE ABSTRACT: This study shows that feticide by intra-amniotic digoxin injection at 21-30 weeks of gestation appears effective and safe.


Assuntos
Aborto Induzido/métodos , Antiarrítmicos/administração & dosagem , Digoxina/administração & dosagem , Morte Fetal , Adulto , Âmnio , Antiarrítmicos/efeitos adversos , Digoxina/efeitos adversos , Feminino , Humanos , Injeções , Gravidez , Resultado da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos
9.
J Oncol Pharm Pract ; 25(7): 1758-1761, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30259783

RESUMO

Drug-drug interactions between digoxin and the triazole antifungal agents, mediated via various cytochrome P450 isozymes, have been described in the literature. Posaconazole is not extensively metabolized by these isozymes but is both a p-glycoprotein (P-gp) substrate and inhibitor. To our knowledge, there have been no published cases of clinically significant posaconazole-digoxin drug-drug interactions. We report an interaction between posaconazole (300 mg by mouth daily) and digoxin (0.25 mg by mouth daily, Monday through Friday) resulting in atrial fibrillation with slow ventricular response and degenerating into polymorphic ventricular tachycardia.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Digoxina/efeitos adversos , Triazóis/efeitos adversos , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Digoxina/administração & dosagem , Interações de Medicamentos , Feminino , Humanos , Triazóis/administração & dosagem
10.
Am J Ther ; 26(1): e54-e65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-26808357

RESUMO

Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.


Assuntos
Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Modelos Biológicos , Área Sob a Curva , Cardiotônicos/administração & dosagem , Digoxina/administração & dosagem , Esquema de Medicação , Interações de Medicamentos , Monitoramento de Medicamentos , Voluntários Saudáveis , Humanos , Modelos Lineares , Masculino , Estudos Prospectivos
11.
Drug Metab Dispos ; 47(2): 71-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30478157

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (-/-) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Digoxina/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Encéfalo/metabolismo , Sistemas CRISPR-Cas/genética , Citocromo P-450 CYP3A/análise , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Digoxina/administração & dosagem , Feminino , Técnicas de Inativação de Genes/métodos , Intestino Delgado/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Modelos Animais , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
12.
Pharm Res ; 36(1): 1, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30402714

RESUMO

PURPOSE: A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition. METHODS: Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined. RESULTS: Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant.


Assuntos
Bupropiona/farmacocinética , Digoxina/farmacocinética , Administração Oral , Animais , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Humanos , Macaca fascicularis , Metaboloma , Metabolômica , Distribuição Tecidual
13.
Int Immunopharmacol ; 65: 174-181, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30316075

RESUMO

Recent findings have demonstrated new therapeutic functions of cardiotonic steroids, a process that is termed drug repositioning. Despite the confirmed anti-inflammatory effects of cardiotonic steroids, their clinical use has been discouraged due to toxicity related to inhibition of the Na+/K+ ATPase. A novel synthetic compound derived from digoxin, 21­benzylidene digoxin (21­BD), does not inhibit this enzyme. Herein, we evaluated the anti-inflammatory and antinociceptive effects and acute toxicity of 21­BD. Murine (Swiss mice) models of paw oedema induced by carrageenan, acetic acid-induced abdominal writhing, and formalin and acute toxicity tests were used. Oral administration of 21­BD (0.3 mg/kg) showed a significant and prolonged inhibition of paw oedema. Histological analysis demonstrated a reduction in inflammatory cells and expression of inducible nitric oxide synthase (iNOS) in footpads 6 h after administration of carrageenan. 21­BD (0.3 mg/kg) also reduced the levels of tumour necrosis factor (TNF)-α 2 and 4 h after carrageenan. 21­BD demonstrated antinociceptive activity, inhibiting abdominal writhes at all tested doses. However, in the formalin test, 21­BD did not present antinociceptive activity. In the acute toxicity test, 21­BD did not cause symptoms of toxicity or mortality. The present study demonstrated, for the first time, that 21­BD is safe and exhibits a marked anti-inflammatory activity in acute local inflammation. This effect might be a consequence of its ability to inhibit the release of the PMN leucocyte-derived mediators, including TNF-α, and iNOS expression as well as its inhibitory effect on oedema and PMN leucocyte infiltration.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Digoxina/análogos & derivados , Analgésicos/química , Animais , Anti-Inflamatórios/química , Carragenina/toxicidade , Digoxina/administração & dosagem , Digoxina/química , Digoxina/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Indometacina/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Testes de Toxicidade , Fator de Necrose Tumoral alfa/metabolismo
15.
Tidsskr Nor Laegeforen ; 138(15)2018 10 02.
Artigo em Norueguês | MEDLINE | ID: mdl-30277048

RESUMO

BACKGROUND: The withdrawal of digitoxin and subsequent substitution with digoxin around 2012 may have led to an increased health risk for patients. The aim of this study was to follow individual patients during the switch. MATERIAL AND METHOD: Serum concentrations of digitoxin and digoxin, measured at the Department of Clinical Pharmacology at St Olavs University Hospital in the period 1 January 2011-31 December 2013 were reviewed. Patients who had switched from digitoxin to digoxin and whose serum concentrations of both drugs had been measured during this period were included. RESULTS: A total of 304 patients, 1686 samples and 1858 serum concentration analyses were included in the study. Therapeutic serum concentrations were measured in 171 patients (56.3 %) before the switch and 176 (57.9 %) after this had taken place. Altogether 108 patients (35.5 %) had therapeutic concentrations both before and after the change. For 58.9 % of the patients, the change resulted in a reduction in serum concentration of digitalis, calculated as digoxin equivalents. The proportion of patients with assumed supratherapeutic concentrations fell from 43.1 % to 33.9 %; however, the proportion of patients with toxic serum concentrations rose from 0.3 % to 3.0 %. INTERPRETATION: Although the switch led to a reduction in dose and serum concentration for many, a significant number of patients may have been put in harm's way.


Assuntos
Antiarrítmicos/sangue , Digitoxina/sangue , Digoxina/sangue , Substituição de Medicamentos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Digitoxina/administração & dosagem , Digitoxina/efeitos adversos , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Monitoramento de Medicamentos , Substituição de Medicamentos/efeitos adversos , Controle de Medicamentos e Entorpecentes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega
16.
J Healthc Eng ; 2018: 3948245, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210752

RESUMO

Digoxin is a high-alert medication because of its narrow therapeutic range and high drug-to-drug interactions (DDIs). Approximately 50% of digoxin toxicity cases are preventable, which motivated us to improve the treatment outcomes of digoxin. The objective of this study is to apply machine learning techniques to predict the appropriateness of initial digoxin dosage. A total of 307 inpatients who had their conditions treated with digoxin between 2004 and 2013 at a medical center in Taiwan were collected in the study. Ten independent variables, including demographic information, laboratory data, and whether the patients had CHF were also noted. A patient with serum digoxin concentration being controlled at 0.5-0.9 ng/mL after his/her initial digoxin dosage was defined as having an appropriate use of digoxin; otherwise, a patient was defined as having an inappropriate use of digoxin. Weka 3.7.3, an open source machine learning software, was adopted to develop prediction models. Six machine learning techniques were considered, including decision tree (C4.5), k-nearest neighbors (kNN), classification and regression tree (CART), randomForest (RF), multilayer perceptron (MLP), and logistic regression (LGR). In the non-DDI group, the area under ROC curve (AUC) of RF (0.912) was excellent, followed by that of MLP (0.813), CART (0.791), and C4.5 (0.784); the remaining classifiers performed poorly. For the DDI group, the AUC of RF (0.892) was the best, followed by CART (0.795), MLP (0.777), and C4.5 (0.774); the other classifiers' performances were less than ideal. The decision tree-based approaches and MLP exhibited markedly superior accuracy performance, regardless of DDI status. Although digoxin is a high-alert medication, its initial dose can be accurately determined by using data mining techniques such as decision tree-based and MLP approaches. Developing a dosage decision support system may serve as a supplementary tool for clinicians and also increase drug safety in clinical practice.


Assuntos
Antiarrítmicos/administração & dosagem , Sistemas de Apoio a Decisões Clínicas , Digoxina/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Aprendizado de Máquina , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/efeitos adversos , Digoxina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Drug Des Devel Ther ; 12: 2139-2147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022812

RESUMO

Background: Previous in vitro studies have reported the inhibitory effect of green tea on p-glycoprotein (p-gp) encoded by ABCB1. This study aimed to investigate the effect of green tea on the pharmacokinetics of digoxin, a typical probe drug of p-gp. Methods: Sixteen healthy volunteers participated in this study. At Day 1, 0.5 mg of digoxin was administered via oral route. After a 14-day washout period, 630 mg of green tea catechins (GTC) was administered via oral route, followed by 0.5 mg of digoxin 1 hour later. From Day 16 through Day 28, 630 mg of GTC was administered alone. At Day 29, 630 mg of GTC and 0.5 mg of digoxin were administered in the same way as Day 15. Blood samples for the pharmacokinetic assessments of digoxin were collected up to 8 hours after each dose. Pharmacokinetic parameters were estimated by noncompartmental analysis. Area under the curve (AUC) and peak plasma concentration (Cmax) were compared using mixed effect model between digoxin alone and digoxin with GTC. ABCB1 was genotyped to determine whether its polymorphism affects digoxin-GTC interaction. Results: Fifteen subjects completed the study. Compared to digoxin alone, the concomitant administration of digoxin and GTC significantly reduced the systemic exposure of digoxin: geometric mean ratios (GMR) and 90% confidence intervals (CI) of area under the concentration-time curve from time 0 to the last measurable time (AUClast) and Cmax were 0.69 (0.62-0.75) and 0.72 (0.61-0.85), respectively. The concomitant administration of digoxin and GTC following pretreatment of GTC (Day 29) similarly reduced the AUClast (GMR [90% CI]: 0.67 [0.61-0.74]) and Cmax (GMR [90% CI]: 0.74 [0.63-0.87]). In the comparison of the percentage changes from Day 1 (digoxin single administration) of AUClast between genotypes, C1236T variant type showed a significant difference to wild-type on Day 15 (concomitant administration of digoxin and GTC) (P=0.005). Conclusion: This study demonstrates that the coadministration of GTC reduces the systemic exposure of digoxin regardless of pretreatment of GTC.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Catequina/farmacocinética , Digoxina/farmacocinética , Extratos Vegetais/farmacocinética , Chá/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Adulto , Catequina/administração & dosagem , Catequina/química , Digoxina/administração & dosagem , Digoxina/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , República da Coreia , Adulto Jovem
18.
Biomed Pharmacother ; 105: 533-539, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29885637

RESUMO

BACKGROUND: Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. METHODS: To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. RESULTS: Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. CONCLUSIONS: These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Digitalis/toxicidade , Digoxina/toxicidade , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Animais , Cálcio/sangue , Digoxina/administração & dosagem , Digoxina/sangue , Eletrocardiografia , Átrios do Coração/patologia , Ventrículos do Coração/patologia , Masculino , Camundongos , Fator de Transcrição RelA/metabolismo
19.
Can J Cardiol ; 34(8): 972-977, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29887217

RESUMO

BACKGROUND: The dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial disorder characterized by progressive cardiomyopathy, prolonged QT interval and early death in childhood related to intractable heart failure. We present a case series of 9 children with DCMA who demonstrated functional improvement and favourable left ventricular remodeling only after digoxin was added to their medical therapy. METHODS: A retrospective review of 46 patients with DCMA followed at the Alberta Children's Hospital from 2005 to 2017 identified 9 patients who were treated with digoxin and had serial echocardiography data. For each subject, we calculated the difference between baseline and follow-up for left ventricular ejection fraction (LVEF), end-diastolic dimension (LVEDD), and end-systolic dimension (LVESD) as determined by echocardiography. RESULTS: Patients were on average 45.6 ± 59 months of age when digoxin was started with a mean LVEF of 40% ± 11% when digoxin was started. Seven patients were on angiotensin-converting enzyme inhibitors (ACEIs) at the time of initiation of digoxin, and all were on ß-receptor antagonists (BB). After being on digoxin for a mean of 11.7 ± 10.9 months, average LVEF improved to 55% ± 10% (P = 0.0005), and there were significant decreases in the Z-scores for LVEDD (+2.1 ± 1.9 to +0.65 ± 1.4, P = 0.02) and LVESD (+3.83 ± 2.07 to +1.79 ± 1.76, P = 0.01). CONCLUSIONS: In children with DCMA, we report that digoxin seems to have additive beneficial properties when combined with ACEI and BB therapy. This novel observation may have implications for the medical treatment of mitochondrial cardiomyopathies.


Assuntos
Ataxia/complicações , Cardiomiopatia Dilatada/tratamento farmacológico , Digoxina/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiotônicos/administração & dosagem , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Síndrome , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
20.
Geriatr Psychol Neuropsychiatr Vieil ; 16(2): 165-171, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29877183

RESUMO

Digitalis remains a treatment that is difficult to manage, especially in the elderly. METHODS: A retrospective, unicentric study carried out within the unit of Internal medicine and geriatrics, Reims University Hospital Center, between January and June 2014. Collection of all patients hospitalized, after 75 years, receiving treatment with digitalis, either as soon as they enter (present on the usual prescription of the patient), during their hospitalization and on their exit. RESULTS: 20 patients were included. The median age was 89 years (range: 78-94). Digitalis was only used in slowing down the ventricular rate during atrial fibrillation; 7 patients (35%) had a high serum digoxin concentration, of which 4 had renal failure. Three patients presented a digital cup on the electrocardiogram. In our series, in digoxin overdosage, 3 patients with electrical signs of digoxin overdosage have all 3 digoxin-beta-blockers. We are in the limit of the significance, for the connection between digoxinemia and the appearance of electrical signs of overdose in digitalis (p=0.06). CONCLUSION: Digoxin therefore remains a drug that is difficult to manage, mainly in the elderly, as there are many clinical, biological drug and therapeutic constraints. Failure to comply with the rules for the use and monitoring of digoxin may prove fatal in the elderly.


Assuntos
Antiarrítmicos/uso terapêutico , Digoxina/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Geriatria , Departamentos Hospitalares/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Monitoramento de Medicamentos , Eletroencefalografia , Feminino , Humanos , Pacientes Internados , Masculino , Conduta do Tratamento Medicamentoso , Estudos Retrospectivos
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