New uses for an old remedy:Digoxin as a potential treatment for steatohepatitis and other disorders

Repurposing of the widely available and relatively cheap generic cardiac glycoside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases.Over the past several years,there have been significant advances in the study of digoxin pharmacology and its potential noncardiac clinical applications,including anti-inflammatory,antineoplastic,metabolic,and antimicrobial use.Digoxin holds promise in the treatment of gastrointestinal disease,including nonalcoholic steatohepatitis and alcoholassociated steatohepatitis as well as in obesity,cancer,and treatment of viral infections,among other conditions.In this review,we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.

舌下含服地高辛对急性心力衰竭的疗效与血清Digoxin RIA变化

充血性心力衰竭急性发作时,临床传统的快速疗法采用静注强心甙,一般为西地兰或毒毛旋花甙K,偶用地高辛,由于采用静脉给药给院外患者特别是家庭与野外等环境下心衰病人的抢救带来一定困难,而口服强心甙往往起效缓慢达不到抢救的目的。为此,我们试用舌下含服地高辛抢救急性发作的心衰病人。现将观察结果报告如下。资料和方法一、临床资料:急性充血性心力衰竭28例(男16例,女12例),年龄28～65岁。原发病因:风湿性心瓣膜病14例,心肌病8例,冠心病6例。心电图诊断快速性房颤13例,窦性心动过速15例。心功能按NYHA分级法:Ⅲ级9例,Ⅳ级19例。全部患者入院前两周内未用过任何洋地黄类药物。二、方法:病人入院后,卧床休息10分钟,使心率稳定。观察(A)组:16例(男8例,女8例)。

Combination of Pretreatments with Acetic Acid and Sodium Methoxide for Efficient Digoxin Preparation from Digitalis Glycosides in Digitalis lanata Leaves

We previously developed an HPLC method for determination of lanatoside C, digoxin and α-acetyldigoxin in digitalis glycosides isolated from Digitalis lanata leaves. Here, we present an improved HPLC-UV method to determine those compounds and deslanoside. We used the improved method to examine the effects of various pretreatments on the amounts of the four compounds isolated from the leaves, with the aim of maximizing the yield of digoxin. Leaves were extracted with 50% methanol, followed by clean-up on a Sep-Pak C18 cartridge prior to HPLC analysis. The amounts of lanatoside C, digoxin and α-acetyldigoxin per 100 mg of the leaves without pretreatment were 115.6, 7.45 and 23.8 μg, respectively (deslanoside was not detected). Pretreatment with acetic acid, which activated deglucosylation mediated by digilanidase present in the leaves, increased the amounts of digoxin and α-acetyldigoxin, while lanatoside C and deslanoside were not detected. Pretreatment with sodium methoxide, which hydrolyzed lanatoside C to deslanoside, increased the yields of deslanoside and digoxin, while lanatoside C and α-acetyldigoxin were not detected. The combination of both pretreatments afforded only digoxin in a yield of 115.1 μg/100 mg leaves. Use of the combined pretreatments appears to be effective for maximizing the yield of digoxin from the leaves.

Digoxin:A systematic review in atrial fibrillation,congestive heart failure and post myocardial infarction

AIM: To review digoxin use in systolic congestive heart failure, atrial fibrillation, and after myocardial infarction. METHODS: A comprehensive Pub Med search was performed using the key words "digoxin and congestive heart failure", "digoxin and atrial fibrillation", "digoxin, atrial fibrillation and systolic congestive heart failure", and "digoxin and myocardial infarction". Only articles written in English were included in this study. We retained studies originating from randomized controlled trials, registries and included at least 500 patients. The studies included patients with atrial fibrillation or heart failure or myocardial infarction and had a significant proportion of patients(at least 5%) on digoxin. A table reviewing the different hazard ratios was developed based on the articles selected. Our primary endpoint was the overall mortality in the patients on digoxin vs those without digoxin, among patients with atrial fibrillation and also among patients with atrial fibrillation and systolic heart failure. We reviewed the most recent international guidelines to discuss current recommendations.RESULTS: A total of 18 studies were found that evaluated digoxin and overall mortality in different clinical settings including systolic congestive heart failure and normal sinus rhythm(n = 5), atrial fibrillation with and without systolic congestive heart failure(n = 9), and myocardial infarction(n = 4). Overall, patients with systolic congestive heart failure with normal sinus rhythm, digoxin appears to have a neutral effect on mortality especially if close digoxin level monitoring is employed. However, most of the observational studies evaluating digoxin use in atrial fibrillation without systolic congestive heart failure showed an increase in overall mortality when taking digoxin. In the studies evaluated in this systematic review, the data among patients with atrial fibrillation and systolic congestive heart failure, as well as post myocardial infarction were more controversial. The extent to which discrepancies among studies are based on statistical methods is currently unclear, as these studies' findings are generated by retrospective analyses that employed different techniques to address confounding. CONCLUSION: Based on the potential risks and benefits, as well as the presence of alternative drugs, there is a limited role for digoxin in the management of patients with normal sinus rhythm and congestive heart failure. Based on the retrospective studies reviewed there is a growing volume of data showing increased mortality in those with only atrial fibrillation. The pro-per role of digoxin is, however, less certain in other subgroups of patients, such as those with both atrial fibrillation and systolic congestive heart failure or after a myocardial infarction. Further studies may provide helpful information for such subgroups of patients.

Digoxin浓度放免测定对老年患者临床探讨

Digoxin是治疗心力衰竭和某些心律失常有效的药物，其安全范围小，个体差异大，半衰期长，是较难驾取的药物之一。临床上中毒率与死亡率仍很高，故合理应用，做到剂量个体化是有意义的，我院对16例按维持疗法服用地高辛的老年患者进行了血清Digoxin放免测定，结果如下。

应用RIA筛选中草药Digoxin含量的初步研究

临床上常用的315种中草药,每种制成汤剂,应用放射免疫分析法(RIA)检测Digoxin含量,结果检出有Digoxin含量者89种,其中最低含量者为22.10ng/L,最高含量者为8000.00ng/L,而对照组其含量为0。抽样23种中草药第1天检测含有Digoxin者贮存在0℃、4℃和室温30天,有14种在三种不同温度贮存后仍可检出Digoxin含量,且首次检出的含量分别与0℃、4℃,室温贮存30天重复检出的含量比较均无显著性差异(p>0.05)。0℃、4℃和室温各组检出的含量之间进行比较亦无显著性差异(p>0.05),因此,表明某些中草药汤剂中Digoxin成分贮存30天仍比较稳定。探索中草药Digoxin含量给提供哪些常用的中草药治疗心衰病人时,防止过量而引起中毒具有一定的临床意义。

Inappropriate use of digoxin in patients presenting with digoxin toxicity

Background Digoxin remains widely used today despite its narrow therapeutic index and toxicity. The objective of this study was to investigate the percentage of inappropriate use of digoxin and long-term outcomes of elderly patients hospitalized for digoxin toxicity. Methods The study included 99 consecutive patients hospitalized for digoxin toxicity. The other study criteria for the inappropriate use of digoxin was regarded if participants having depressed left ventricular systolic function （ejection fraction 〈 45%） who were not on optimal medical therapy including beta-blocker and angiotensin-converting-enzyme inhibitor therapy or if participants having permanent AF who were not on optimal beta-blocker therapy. Results Appropriate digoxin usage was confirmed in 33 of patients in spite of its narrow therapeutic index. A total of 16 of 99 patients died, with a mean follow-up time of 22.1 ± 10.3 months. Conclusions Contrary to popular belief, the rate of inappropriate digoxin usage remains high. On account of its narrow therapeutic index and toxicity, digoxin should be used more carefully according to the current evidence and guidelines.

Clinical Study on Chronopharmacokinetics of Digoxin in Patients with Congestive Heart Failure

Fluorescence polarization immunoassay was used to study the chronopharmacokirietics of digoxin in 10 patients with congestive heart failure (CHF) who also served as self-controls. Our results showed that the serum digoxin concentration reached peak value 1h after taking digoxin at 7: 00 a. m.,but the serum digoxin concentration reached the peak value 2 h after taking digoxin at 4: 00 p. m.. The average serum digoxin concentration area under curve was greater and the best maintainable time of serum concentration within 24 h after taking digoxin at 4 p. m. longer than those at 7: 00 a. m.. The heart rates were obviously lower and the cardiac function was significantly improved in 4:00 p. m.group.

Safety of digoxin in nonagenarian patients with atrial fibrillation:lessons from the Spanish Multicenter Registry

BACKGROUND The association between digoxin and mortality is an unclear issue.In older patients with atrial fibrillation(AF),where use of digoxin is frequent,the evidence of its safety is scarce.Our aim is to assess the safety of digoxin in nonagenarian patients with AF.METHODS We evaluated data from 795 nonagenarian patients with non-valvular AF from the Spanish Multicenter Registry.We analyzed the relationship between digoxin and all-cause mortality with the Cox proportional-hazards model.RESULTS Follow-up was 27.7±18.3 months.Mean age was 92.5±3.8 years,and 71%of nonagenarian patients were female.Digoxin was not associated with increased risk of mortality[adjusted hazard ratio(aHR)=1.16,95%CI:0.96−1.41,P=0.130].However,we found a significant increase in mortality in the subgroup with estimated glomerular filtration rate(eGFR)<30 mL/min per 1.73 m^(2)(aHR=2.01,95%CI:1.13−3.57,P=0.018),but not in the other subgroups of eGFR(30−59 mL/min per 1.73 m^(2) and≥60 mL/min per 1.73 m^(2)).When exploring the risk of mortality according to sex,male subgroup was associated with an in-crease in mortality(aHR=1.48,95%CI:1.02−2.14,P=0.041).This was not observed in females subgroup(aHR=1.03,95%CI:0.81−1.29,P=0.829).Based on the presence or absence of heart failure,we did not find significant differences(aHR=1.20,95%CI:0.87−1.65,P=0.268 vs.aHR=1.15,95%CI:0.90−1.47,P=0.273,respectively).CONCLUSIONS In our large registry of nonagenarian patients with AF,we did not find an association between digoxin and mortality in the total sample.However,in the subgroup analyses,we found an increase in mortality with the use of digoxin in men and in patients with an eGFR<30 mL/min per 1.73 m^(2).

老年心脏病患者Digoxin应用量探讨

Digoxin为洋地黄类强心药,多年来广泛应用于临床各种类型心脏病所致的心力衰竭及某些心律失常,为疗效好的强心药。85％由肾脏排出,由于其治疗量与中毒量接近,故从临床上应对其中毒问题加以重视。目前在我国老年心脏病患者中用药情况,亦在探讨中。

Digoxin and Heart Failure:Are We Clear Yet?

The Digoxin Investigation Group trial has multiple flaws in the trial design for the fi ndings to be universally applicable.Digoxin in low serum concentrations(0.5-0.9ng/mL)has been shown to decrease mortality in heart failure patients.Multiple trials in different patient populations also show benefit of digoxin in heart failure patients,including women,elderly patients,renal disease patients,and patients with heart failure with preserved ejection fraction.Retrospective observational data linking digoxin use for treatment of atrial fi brillation to increased mortality is not seen in subgroups of randomized controlled trials or population registries.Digoxin remains a useful drug in the toolbox of physicians dealing with heart failure patients.

Digoxin intoxication： An old enemy in modern era

Objectives Although development of new treatment modalities limited digoxin usage, digoxin intoxication is still an important issue which could be easily overlooked. In this report, we analyzed a case series definitively diagnosed as digoxin intoxication in the modern era. Methods We analyzed 71 patients hospitalized with digoxin intoxication confirmed by history, complaints, clinical and electrocardiograph （ECG） findings, and serum digoxin levels 〉 2.0 ng/mL, during a five year period. The demographic and clinical data, indications for digoxin use, digoxin dosage, concurrent medications, laboratory data, hospital monitoring, and ECG findings were obtained from all patients. Results Thirty-eight of 71 patients （53.5%） had symptoms of heart failure during admission or later. Sixty-four percent of patients were older than 75 years. The percentage of females was 67%. Atrial fibrillation, hypertension and gastrointestinal complaints were more frequent in the females （64% in females, 30% in males, P = 0.007; 81% in female, 52% in males, P = 0.01; 50% in female, 17.3% in males, P = 0.008, respectively）. The mortality rate during the hospital course was 7%. Conclusions This report demonstrated the reduced mortality rates in patients with digoxin intoxication over the study period. Gastrointestinal complaints are the most common symptoms in this population.

EFFECTS OF OUABAIN AND DIGOXIN ON THE GENE EXPRESSION OFSODIUM PUMP α-SUBUNIT ISOFORM IN AORTIC SMOOTH MUSCLE OF RATS

Objective To compare the effects or ouabain and digoxin on both the systolic blood pressure and sodium pump a-subunit isoforms gene expression in the aortic smooth muscle of rats. Methods Normal Sprague- Dawley rats were injected with ouabain (20μg·kg-1·d-l,i. p), digoxin (32 μg·kg-1·d-1, i. p)and normal saline once a day, respectively, and indirect systolic blood pressure was recorded once a week. Six weeks later,all the rats were killed and sodium pump α1-,α2-,and α3-subunit mRNA levels were detected in the aortic smooth muscle with reverse transcription polymerase chain reaction（RT-PCR） method. Results The systolic blood pressure of rats infused with ouabain increased significantly at the end of week 6 [l32. 6±9.0 mmHg （1 mmHg = 0. 133 kPa） vs 115. 7 ± 8. 2 mmHg, P <0.01],while no difference of blood pressure was found between digoxin group and NS group （P>0.05）. The expression or sodium pump α-subunit isoforms in aortic smooth muscle was regulated by either ouabain or digox- in:both ouabain and digoxin increased α1- and α3-subunit expression, α2-subunit decreased in digoxin group but un- changed in ouabain group. Conclusion These results suggest that both ouabain and digoxin could regulate sodium pump α-subunit isoform expression, which might be related to the physiological roles or endogenous ouabain and might be responsible for the difference between the pharmacological and toxicological effects or ouabain and digoxin, including their effects on blood pressure.

Evaluating the regulation of transporter proteins and P-glycoprotein in rats with cholestasis and its implication for digoxin clearance

BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.