Clinical Use of Digitalis: A State of the Art Review.

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

[New pharmacologic therapies for chronic heart failure]. / Neue medikamentöse Therapieansätze bei chronischer Herzinsuffizienz.

Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life.

[Considerations about study on mechanisms of acupuncture underlying efficacy-enhancement and toxicity-attenuation of digitalis drugs for heart failure].

Digitalis glycosides, a group of cardiotonic agents for heart failure, have been used for a long time, but may often trigger arrhythmias as a result of digitalis intoxication. It is of great significance in finding a method to reduce their toxicity and improve clinical curative effects simultaneously in the application of digitalis glycosides. It has been well documented that acupuncture has good therapeutic effects in improving cardiac function and inhibiting arrhythmia induced by myocardial ischemia. Acupuncture combined with chemotherapeutics can reduce the adverse effects of chemotherapeutics. Accordingly, acupuncture combined with digitalis is likely to reduce the side effects of digitalis by regulating intracellular Ca2+, improving the function of Ca(2+)-ATPase in the sarcoplasmic reticulum, increasing calcium sensitivity of cardiac troponin, etc. These considerations may provide a novel clue for treatment of heart failure by joint administration of acupuncture and drugs.

A fond farewell to the foxglove? The decline in the use of digitalis.

Since William Withering's report on the foxglove in 1785, digitalis, in 1 form or another, has remained a mainstay in the treatment of congestive heart failure and as a means of rate control in atrial fibrillation. Recently, with the introduction of potent diuretics and other agents for the treatment of these conditions, there has been a deemphasis on the role of digitalis despite its therapeutic value. Continued evidence of the frequent usefulness of digitalis in both conditions suggests that this venerable drug should remain within the therapeutic armamentarium of cardiologists and other physicians.

[The clinical efficacy and safety study of Esculin and Digitalis glycosides Eye Drops in treating ametropic asthenopia].

OBJECTIVE: To study the clinical efficacy and safety of the Esculin and Digitalis glycosides Eye Drops used in the patients of ametropic asthenopia. METHODS: Multicenter clinical trial. Asthenopia patients were chosen from eleven hospitals cross China from July, 2008 to January, 2009. The experiment was conducted asthenopia patients who used the Esculin and Digitalis glycosides Eye Drops for 4 weeks continuously. Symptoms of asthenopia, UCVA (uncorrected vision acuity), refraction, amplitude of accommodation, accommodative lag, accommodative sensitivity and positive/negative relative accommodation were measured at different time points, such as treated before, 1 week and 4 week in treated after. RESULTS: After the 4-week's use of Esculin and Digitalis glycosides Eye Drops, each subjective symptom of the patients was decreased significantly (F=353.30, P<0.05). In addition, most of the objective exams of accommodation ability were significantly improved, such as UCVA (left eye: F=23.39, P<0.05; right eye: F=15.62, P<0.05), refraction (left eye: F=10.34, P<0.05; right eye: F=17.13, P<0.05), amplitude of accommodation (left eye: F=14.46, P<0.05; right eye: F=8.29, P<0.05; eyes: F=13.86, P<0.05), accommodative lag (F=14.89, P<0.05) and accommodative sensitivity (left eye: F=62.67, P<0.05; right eye: F=68.77, P<0.05; eyes: F=82.74, P<0.05). And no patient appeared any adverse reaction in whole experiment. CONCLUSIONS: Esculin and Digitalis glycosides Eye Drops is effective and safety for use in the patients of ametropia asthenopia.

Digitalis, a targeted therapy for cancer?

The clinical benefit of digitalis for patients with heart disease is well established. However, recent studies have also suggested that digitalis has antineoplastic activities at clinically relevant serum concentrations. Much of the early evidence supporting the anticancer activity of digitalis has been circumstantial. Observational studies suggest a protective benefit and improved outcomes in patients who develop cancer while they are taking digitalis. The mechanism by which digitalis selectively affects the growth of malignant cells is complex, involving several important signaling pathways. Experiments to determine its mechanism of action have demonstrated that digitalis inhibits cell growth and angiogenesis and induces apoptosis in multiple cancer cell lines. Most, if not all, of these effects are mediated through its target enzyme, sodium- and potassium-activated adenosine triphosphatase. This article reviews the literature, which supports the use of digitalis in patients with malignancies with a discussion of the potential mechanisms of action. We hypothesize that sodium- and potassium-activated adenosine triphosphatase is an important new target for cancer therapy. It is reasonable to expect that the addition of digitalis to current cancer treatments will improve the clinical outcomes.

[Milestones of cardiovascular pharmacotherapy: II. Digitalis]. / Milníky kardiovaskuláirní terapie II. Digitalis.

Several plant extracts containing cardiac glycosides have been used in the treatment of dropsy (oedemas) for many centuries. When William Withering 1785 published his book "An account of the foxglove and some of its medical uses", he was aware that digitalis is effective only in certain medical forms of dropsy but did not associate this effect with the cardiac action of the drug. However, he recognised that "the motion of the heart was affected". Although clinical experience, experimental data and haemodynamic studies supported the use of digitalis for the treatment of heart failure, repeated controversies surrounded its efficacy and appropriated indication. At the end of the last century, the issue was not whether digoxin is effective, but whether it has a role in patients with sinus rhythm treated with ACE-inhibitors and in heart failure with preserved systolic function. In 1993, two studies that assessed the effect of digoxin withdrawal noted adverse effects after discontinuation: In the RADIANCE Study, digoxin withdrawal was associated with significant worsening of heart failure and decrease in exercise capacity and LVEF, and the PROVE Trial provided strong evidence of digoxin efficacy in patients with systolic dysfunction and sinus rhythm. In the DIG Study (1997) digoxin reduced the rate of hospitalisations but did not significantly improve the survival. The reevaluation of this study by Ahmed et al. (2006), however, demonstrated that digoxin reduces mortality and hospitalisation rate in all patients including those with preserved systolic function if used in doses of 0.125-0.250 mg reaching the SDC of 0.5-0.9 ng/ml. The authors conclude that digoxin should be prescribed before adding ACE-inhibitors, angiotensin receptor blockers, aggressive diuretic therapy and before considering cardiac resynchronisation therapy, thus rehabilitating the physiological approach to the treatment of chronic heart failure, starting the treatment by restriction of physical activity and digitalis, as practised before introduction of oral diuretics, and newly suggested by Braunwald 1980. It is a logical inexpensive approach.

Pharmacologic prophylaxis for postoperative atrial tachyarrhythmia in general thoracic surgery: evidence from randomized clinical trials.

BACKGROUND: Atrial tachyarrhythmia is the most common complication after general thoracic surgery and is associated with significant morbidity, longer hospital stay, and higher costs. We sought to determine whether the use of antiarrhythmic medications is associated with a reduced rate of postoperative atrial tachyarrhythmia. METHODS: MEDLINE, EMBASE, Cochrane Database of clinical trials (1980-2003), and reference lists of relevant articles were searched for randomized controlled trials with placebo control, general thoracic patients, and noncombined and prophylactic use of the medications. Search, data abstraction, and analyses were performed and confirmed by at least 2 authors. A fixed-effects model was used to perform meta-analyses. RESULTS: There were 11 unique trials (total n = 1294) that met the inclusion criteria. Calcium-channel blockers and beta-blockers reduced the risk of atrial tachyarrhythmia in 4 and 2 trials, respectively (relative risk of 0.50 and 95% confidence interval of 0.34-0.73; relative risk of 0.40 and 95% confidence interval of 0.17-0.95, respectively). However, beta-blockers tended to increase the risk of pulmonary edema (relative risk, 2.15; 95% confidence interval, 0.74-6.23). Magnesium tested in one unblinded trial also reduced the risk of atrial tachyarrhythmia (relative risk, 0.4; 95% confidence interval, 0.21-0.78). On the other hand, digitalis preparations were found to be harmful because they increased the risk of atrial tachyarrhythmia in 3 trials (relative risk, 1.51; 95% confidence interval, 1.00-2.28). Finally, 2 other medications, flecainide and amiodarone, were each tested in a single small trial, and their effects were associated with great uncertainty. CONCLUSIONS: Calcium-channel blockers and beta-blockers are effective in reducing postoperative atrial tachyarrhythmia. The use of these medications should be individualized, and possible adverse events of beta-blockers should be taken into account. Randomized clinical trials do not support the use of digitalis in general thoracic surgery. The value of magnesium as a supplement to a main prophylactic regimen should be explored.

[Study on effect of Astragalus injection in treating congestive heart failure].

OBJECTIVE: To observe the clinical efficacy and side-effects of Astragalus Injection (AI) in treating congestive heart failure (CHF). METHODS: Eighty-three patients of CHF with heart function of II-IV grade assessed by NYHA (New York Heart Association) classification were randomly divided into 2 groups. The 42 patients in the treated group were treated with AI 40 ml (equivalent to 80 g crude drug) by adding in 5% glucose solution 500 ml for intravenous dripping, once a day and the 41 patients in the control group were treated by nitrolingual injection 15 mg by adding in 5% glucose solution 500 ml for intravenous dripping once a day. The therapeutic course in both groups was 2 weeks and the patients were followed-up for 1-6 months. RESULTS: The clinical heart function improvement rate and the total effective rate in the treated group after 1 month treatment were 26.2% and 78.6%, and after 6 months were 34.2% and 81.6% respectively, which were superior to those in the control group significantly (P < 0.05 or P < 0.01). The levels of left ventricular ejection fraction (LVEF), fractional shortening of left ventricular short axis (FS), the ratio of maximum blood flow between the advanced and early atrial systole (E/A), stroke volume (SV), cardiac output (CO) and the cardiac index (CI) were all improved in both groups (P < 0.01 or P < 0.05), but better improvement was shown in the treated group. Follow-up study showed that the incidence of cardiac event was lower in the treated group than that in the control group (P < 0.05). CONCLUSION: AI can be took as one of the important auxiliary drugs for treatment of CHF especially in severe cases.

[Digitalic therapy. Historical outline]. / Acerca de la terapéutica digitálica. Bosquejo histórico.

The action of medical drugs obtained from many vegetables aroused a great interest of naturalists and physicians in all time. Moreover, it was always required that those persons destined to medical practice have a good knowledge of botany. Among the medicinal plants utilized by ancient peoples of the Anahuac, yoloxochitl or heart flower (Talauma mexicana) is mentioned, which seems to have a digitalis-like action. Research in our century demonstrated a positive inotropic and bradycardic effect of the leavels of Magnolia grandiflora or Talauma mexicana extract. Since the end of the XVIII century, digitalis was employed. It was considered initially as a diuretic and later as a cardiotonic agent. The action of digitalic glycosides upon the cardiac tissues was studied experimentally in Mexico. At the present-time there are positive inotropic agents derived from pyridine, as is the case of Milrinone, which have a beneficial action on the failing human myocardium. However, following the opinion of distinguished pharmacologists, "in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted".

[Digitalis intoxication during the neonatal period: role of dehydration]. / Intoxication digitalique en période néonatale: rôle de la déshydratation.

BACKGROUND: Despite the great progress which has been made in the treatment of acute digitalis intoxication by digoxin-immune Fab, it still remains a severe complication of cardiotonic therapy. CASE REPORT: A neonate with ventricular septal defect and large left-to-right shunt was treated with digitalis and diuretics at the usual starting doses. An intensive phototherapy was also required because of a hyperbilirubinemia due to glucose-6-phosphate dehydrogenase deficiency. Toxic digoxin accumulation (plasma level 14 ng/mL) was diagnosed three days after the initiation of treatment by the presence of sinus bradycardia and bursts of ventricular fibrillation. Intravenous administration of digoxin-specific antibody Fab fragments (Digidot) was effective, with a rapid improvement of the digitalis poisoning. CONCLUSION: Because of the particularities concerning drug distribution, metabolism and elimination of drugs in the neonatal period, the digoxin therapeutic index is narrow. This case report suggests the involvement of phototherapy and diuretics, which might induce a significant decrease in extracellular water and drug distribution volumes, ultimately promoting the occurrence of an intoxication.

[Prognosis and treatment of chronic cor pulmonale]. / Pronostic et traitement du coeur pulmonaire chronique.

We have report one hundred cases of chronic pulmonary heart observed between 1982 and 1991. Mean age was 63 years, 61% were men. COPD was the most frequent etiology of CP (84%) before restrictive (14%) and thromboembolic diseases (2%). Diuretics were used in all patients, nifedipine in 32% and digitalis in 16%. Eleven patients died during their first admission, and six died later. Only 31 patients are still regularly.

Digitalis and heart failure: does digitalis really produce beneficial effects through a positive inotropic action?

Although digitalis was introduced to medicine long ago, the drug is still extensively used in clinical practice today. Opinions on its mechanism of action have undergone much change in the course of time, and the way in which cardiovascular effects are produced is still not completely clear. Limitations and contraindications for the use of digitalis substances are reported, especially in the treatment of ischemic heart disease. Preliminary data regarding the effects of digitalis on the diastolic phase are unfavorable, although the relationship between digitalis and diastolic function ought to be studied in greater depth in various clinical conditions. In spite of many recent trials, the old question of the usefulness of digitalis in the chronic treatment of patients in sinus rhythm and heart failure is still debated. An important clinical benefit in the chronic use of digitalis appears restricted to a relatively small proportion of patients with severe congestive heart failure, while in the majority of chronically treated subjects the effects of the drug are scanty or insignificant. The beneficial effect of digitalis used chronically is essentially believed to be due to its positive inotropic action. Since the vagomimetic and the antiadrenergic effects of digitalis have been demonstrated to be independent from its inotropic action, they could be considered determinants of the clinical benefits of digitalis. These indirect effects may be useful in the control of the negative neuroendocrine response developing during congestive heart failure. Thus the statement that digitalis is essentially an inotropic agent seems restrictive; its definition should reflect the favorable effects obtained in some cases of congestive heart failure rather than its various and contrasting underlying mechanisms of action.