Digitalis Preparations Research Articles

Whither digitalis? What we can still learn from cardiotonic steroids about heart failure and hypertension.

Cloning of the "Na+ pump" (Na+,K+-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.

Sensitive liquid chromatography/tandem mass spectrometry method for the simultaneous determination of seventeen beta blockers

In recent years, examples of drugs responsible for acute drug intoxication in elderly people include benzodiazepines, phenobarbital, digitalis preparations, phenytoin, beta blockers or calcium antagonists, and antidepressants in Japan. Due to the diversity of underlying diseases, the reasons for this include increasing number of prescription medicines due to regular oral medicines themselves interacting, and age-related changes in drug metabolism. Beta blockers for clinical use are employed in the management of a range of disorders, including hypertension, heart failure, arrhythmias, migraine headache and tremor. Beta blockers are prescribed widely and also have a high frequency of accidental ingestion by the elderly people. Cardiovascular drugs (beta blockers) present more serious symptoms of intoxication than the underlying diseases themselves. The aim of this study is to develop and validate a sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) with ESI method for the simultaneous determination of seventeen beta blockers (atenolol, carteolol, nadolol, pindolol, timolol, acebutolol, arotinolol, metoprolol, esmolol, celiprolol, labetalol, bisoprolol, propranolol, alprenolol, betaxolol, bevantolol and carvedilol). The extractions of beta blockers in human serum were performed by solid-phase extraction method using Oasis® PRiME HLB column (Waters). LC-MS/MS experiments were performed with a HPLC system, which consisted of Shimadzu LC-20AD pumps, a SIL-20AC autosampler and the 4000 QTRAP mass spectrometer (AB SCIEX). The chromatographic separation was performed on a Mightysil-RP-18 MS column (150 × 2.0-mm i.d., 5 μm). For the gradient elution, two solvents were used: (A) 10 mM acetic ammonium buffer and (B) acetonitrile. The flow rate was 0.20 mL/min and the column and autosampler were maintained at 37 and 4˚C, respectively. The settings of the turbo ion-spray were as follows; curtain gas, N2:40 psi, collision gas, N2:4 psi, collision energy: 27∼41 V, ion-spray voltage: 5500 V, ionization mode: ESI positive, source temperature: 600˚C. Separation and sensitivity for the detection of seventeen beta blockers by LC-MS/MS were sufficient and the precursor [M + H]+ ion was detected in the mass spectrum for each drug. This method had a chromatographic total run time of 15 min. The calibration curves were linear over the concentration range of 20–400 ng/mL for seventeen beta blockers (r = 0.9686∼0.9997). The extraction yields of human serum sample with Oasis® PRiME HLB column were ranged from 66.1 to 93.5%, the precision within 0.07 CV values were acceptable of this method. But the extraction yields of bevantlol (37.5%) and carvedilol (26.2%) were low. Currently, we are experimenting to improve the extraction yields of bevantolol and carvedilol. Phyo Lwin EM, et al (2017, Bioanalysis.) developed a method for the determination of atenolol in human plasma and milk sample by LC-MS/MS. The limits of detection (LOD) and quantification (LOQ) were in the range 1.0 ng/mL and 5.0 ng/mL for atenolol. Our LC-MS/MS with ESI method was able to measure compounds at approximately the same concentrations as the analytical methods of Phyo Lwin EM, et al. In our experiments, LOD and LOQ in the range 0.0034–1.6 ng/mL and were 20 ng/mL for seventeen beta blockers. The presently established method is very useful for simultaneous measurements of beta blockers in human serum by LC-MS/MS in clinical and forensic investigations.

Designing and construction of genetically encoded FRET-based nanosensor for qualitative analysis of digoxin

Nanobiotechnological improvements defined on the utilization of biological materials and principles have enormously partaken to revolutionize physical, chemical, and biological sciences. However, the exploration of plant nanobiotechnology is still in its outset. The search for novel tools to monitor plant biomolecules is an emerging issue for the nanobiotechnologists. Given this, a genetically encoded FRET-based nanobiosensor has been developed to monitor the popular plant cardiac glycoside – digoxin, which is used as the most common prescription drug for heart-related illnesses across the world. Digoxin is sourced from the leaves of the foxglove plant (Digitalis purpurea L.) and has a significant demand in the medical sector. Moreover, with the rising popularity of the herbal formulations in the global market, attention towards the authentication and quality control of the herbal drugs is important. Furthermore, digoxin has a very narrow therapeutic range, i.e., 0.6 nM - 2.6 nM. Therefore, strict monitoring of blood digoxin levels is necessary. Besides, previously used techniques for drug authentication and quantification of small-molecule drugs in blood samples are not the best choice available. The nanobiosensor is based on the FRET (Fluorescence Resonance Energy Transfer) mechanism, and it is constructed in such a way that it gives a changed FRET output in the presence of digoxin. Two fluorophores, enhanced cyan fluorescent protein (ECFP) and Venus, were attached on either end of the sensory domain - human nuclear receptor ROR-gamma (RORγt). The developed nanobiosensor was named as fluorescent indicator protein for digoxin, (FLIP-digoxin). The ligand binding affinity of FLIP-digoxin was calculated as 425 μM. Affinity mutants of the FLIP-digoxin were also generated to measure digoxin in wide concentration ranges. This sensor offers high-throughput qualitative analysis of digoxin in Digitalis preparations procured from local drug stores. It confirms the authenticity of the preparations through the detection of digoxin. The FLIP-1n was also able to monitor digoxin concentration in serum samples in lesser than 5 min. The nanobiosensor was found pH stable, digoxin-specific, non- interfered by the biological serum species and can perform high throughput screening of the Digitalis powder, infusion and tincture preparations.

Features of approaches to the treatment of secondary hypokalemic paralysis in emergency neurology. Review

Secondary hypokalemic myoplegia may be due redistribution of potassium between extracellular and intracellular fluid, loss of potassium through the gastrointestinal tract, elevated renal excretion of potassium. Mortality in hypokalemic myoplegia is determined by fatal cardiac arrhythmias, in patients, as a rule, suffering from a pathology of the cardiovascular system (ischemic heart disease, chronic heart failure, left ventricular hypertrophy), respiratory failure. The emergence of prognostically unfavorable rhythm disturbances (ventricular fibrillation, bigeminy, trigymenia, “pirouette” ventricular tachycardia) is provoked by even a slight K deficiency in the blood (less than 3.5 mmol/l). The arrhythmogenic effect of hypokalemia is potentiated by taking digitalis preparations. With ventricular arrhythmias that have arisen on the background of hypokalemia, emergency therapeutic measures are required to restore the content of potassium in the blood serum. The most effective is the use of a diet rich in potassium in combination with taking potassium chloride or potassium-saving diuretics. Late arrest of cardiac arrhythmias with hypokalemic myoplegia, especially in patients with cardiovascular pathology, determines an increase in the frequency of deaths.

Protective effects of Hawthorn (Crataegus oxyacantha) extract against digoxin-induced arrhythmias in rats.

Objective:Digitalis preparations are commonly used by children and adults with heart diseases worldwide, although excessive doses may cause cardiac effects. The aim of the study is to evaluate the antiarrhythmic effect of Crataegus oxyacantha extract on digoxin-induced arrhythmias in anesthetized Wistar rats.Methods:Control and experimental groups were evaluated for arrhythmias induced by digoxin. Fifteen rats (7 as controls and 8 as the experimental group) were included in the study. The dry fruits of 100 mg Crataegus oxyacantha were extracted by percolation method. Digoxin, at a dose of 40 μg/kg/min, was infused to form the arrhythmias in all rats. Simultaneously, the extract was infused into the experimental group, while 0.9% NaCl was infused into control group. Electrocardiographic QRS prolongation and arterial blood pressure changes were analyzed.Results:The experimental group lived longer (62.13±2.20 min) than the controls (p=0.002). On the other hand, the time to beginning of QRS prolongation did not differ between the two groups (p=0.812). Bradycardia was significant in the control group (288.01±10.54 beat/min and p=0.01). The maximum QRS duration was observed in the control group during the digoxin and 0.9% NaCl infusion period (53.29±3.99 ms and p=0.001). Also, the durations of atrial and ventricular arrhythmias were shorter in the experimental group. However, arterial blood pressure dipping was significant in the experimental group (23.67±10.89 mm Hg and p<0.001).Conclusion:Crataegus oxyacantha alcoholic extract produced an antiarrhythmic effect that was induced by digoxin in Wistar rats. However, in the clinical use of this extract, the hypotensive effect should be considered. Also, the alcoholic extract of Crataegus oxyacantha may be an alternative treatment medication for arrhythmias induced by digoxin toxicity in humans.

ABFM'S HEART FAILURE SELF-ASSESSMENT MODULE SIMULATION ACTIONS VIS-A-VIS GUIDELINE RECOMMENDATIONS

The American Board of Family Medicine (ABFM) introduced Maintenance of Certification for Family Physicians (MC-FP) in 2004 in response to policy adopted by the American Board of Medical Specialties (ABMS.)1 ABFM reported in 2006 the initial Diplomate experiences with MC-FP.2 At that time, ABFM had Self-Assessment Modules (SAMs), consisting of a 60-item knowledge assessment followed by a virtual patient clinical simulation available only for hypertension, type 2 diabetes mellitus, asthma, and depression. Since that time, ABFM has deployed modules for coronary artery disease, chronic heart failure, well child care, maternity care, preventive care, care of the vulnerable elderly, pain management, early childhood illness, cerebrovascular disease, and health behavior. Each of the SAMs includes a Diplomate assessment of both the knowledge assessment and the simulation components. In addition to the Diplomates’ subjective assessments of the SAMs, ABFM captures the actions taken during each simulation, including the action itself, the simulated date and time of the action, and the simulated patient’s current health state. This information is captured in an action log, which serves as a persistent record of the Diplomate’s traversal through the simulation scenario. ABFM introduced the chronic heart failure (CHF) SAM and associated simulation in 2006. We present in Figure 1 a graphical summary of simulation actions taken in the CHF SAM, as extracted from the simulation action logs from 2006 to 2011. We present the results as percentage of simulations in which given actions occurred. Figure 1 Chronic heart failure Self-Assessment Module simulations including indicated actions. The results indicate overall high use of angiotensin converting inhibitors (ACEInhibitors), ACE inhibitors and/or angiotensin receptor blockers (ACEInhibitor-sARBS), but surprisingly low use of beta-adrenergic blocking agents (BetaBlockers.) Digitalis preparations (DigitalisPrep) demonstrated very low use. The majority of Diplomates also did a formal assessment of left ventricular function (Echocardiogram.) The CHF simulations generally present scenarios representing patients with stage C heart failure, as defined in the 2009 ACCF/AHA heart failure guideline.3 According to that guideline, ACE inhibitors and beta-adrenergic blockers should routinely be used in these patients.3 This discrepancy between recommended therapy and the low percentage of beta-adrenergic blocker prescriptions in the simulations suggests that the knowledge assessments should perhaps place greater emphasis on the use of these agents in class C .heart failure. The current CHF knowledge assessment contains only 7 items that reference beta-blockers, and nearly all of these present a beta-adrenergic agent only as historical information in the clinical stem of the item, rather than as a focus of decision-making in the item. These results suggest that the simulations, although clearly presenting a virtual patient environment, can serve as a useful probe for identifying possible management gaps that should be emphasized in the SAM knowledge assessments.

Rate Control in Atrial Fibrillation

Controlling the ventricular rate during both paroxysmal and persistent atrial fibrillation (AF), initially with digitalis preparations and subsequently with β-blockers and calcium channel blockers, has been a mainstay for the management of this arrhythmia for many years. With the advent of a wide range of pharmacological and nonpharmacological approaches for maintaining sinus rhythm, rhythm control strategies have entered widespread clinical use in selected subsets of symptomatic patients. Despite the availability of these rhythm control strategies, however, rate control of AF remains an important and useful approach for a large number of patients, especially those with little or no symptoms from the arrhythmia once the ventricular rate has been controlled. This review discusses the relative risks and benefits of rate versus rhythm control strategies, describes the targets and available methods for rate control, and highlights special considerations for ventricular rate control when cardiac resynchronization therapy (CRT) is used in patients with AF. Among the most important decisions that must be made by a patient and care provider when choosing a treatment plan for AF is the choice between rate and rhythm control. Rate control is typically a simpler strategy than rhythm control, involving the use of generally less toxic medications and fewer medical procedures, although rate control strategies can result in adverse drug side effects and toxicities and, in some cases, may require interventions such as pacemaker implantation and atrioventricular (AV) nodal ablation. Rhythm control strategies typically involve potentially riskier antiarrhythmic medications or invasive procedures such as catheter ablation or surgery, but, when successful, provide the benefits of sinus rhythm. ### Randomized Trials of Rate versus Rhythm Control Several large randomized, controlled clinical trials have been performed to compare the risks and benefits of rate versus pharmacological rhythm control strategies in patients with AF. Among these are the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM), Rate Control Versus …

Reconsidering the Role for Digoxin in the Management of Acute Heart Failure Syndromes

THE USE OF DIGITALIS PREPARATIONS FOR TREATMENT of cardiac maladies has been debated for centuries. Controversy regarding their effect on mortality has been the primary issue, given their relatively narrow toxic-therapeutic ratio. This led to the Digitalis Investigation Group trial, organized and conducted by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs. The trial, which involved patients with chronic heart failure and in sinus rhythm, demonstrated that, although digoxin did not affect survival, it was effective at reducing hospitalizations of patients receiving standard therapy—consisting of diuretics and angiotensinconverting enzyme (ACE) inhibitors—for heart failure. As a result, the US Food and Drug Administration granted regulatory approval to digoxin for the treatment of heart failure and atrial fibrillation in 1997. However, available data from registries and clinical trials of heart failure suggest that digoxin use has decreased considerably, from approximately 80% to 30% in the last 10 years. Several factors may have contributed to this decreased use of digoxin. Digoxin has received little attention at large cardiology meetings; has not been promoted by the pharmaceutical industry, given the very low cost of this generic drug; and has been supplanted by the introduction of life-saving therapies for heart failure including -blockers, angiotensin-receptor blocking agents, aldosterone-blocking agents, and cardiac resynchronization therapies. Moreover, retrospective studies of the Digitalis Investigation Group trial raised serious safety concerns, particularly for women, which may have further contributed to the decreased use of digoxin. Forgetting a drug is not necessarily a tragedy. In the last decade, however, registries and trials of acute heart failure syndromes resulting in hospitalization have shown mortality and rehospitalization rates as high as 15% and 30%, respectively, within 90 days of discharge. This high event rate occurred in patients already receiving evidence-based therapies, including loop diuretics, -blockers, ACE inhibitors, and angiotensin-receptor blockers. Although the main reason for heart failure–related admission and readmission results from hemodynamic instability due to a high left ventricular filling pressure, low cardiac output, or both, every new agent tested to date known to improve hemodynamics in acute heart failure syndromes has not been shown to be either efficacious or safe. In the last 15 years, only nesiritide has been approved by the Food and Drug Administration for acute heart failure syndromes, even though safety issues for nesiritide were raised after it was approved, including renal function impairment and, more importantly, mortality. The most recently evaluated agent, rolofylline, an adenosine-blocking agent, did not demonstrate clinical benefit and showed an increase in central nervous system events. With this background, the role of digoxin in acute heart failure syndromes should be reexamined. What would be an ideal agent for treatment of acute heart failure syndromes? Such a drug should (1) improve hemodynamics without adversely affecting heart rate or blood pressure or increasing myocardial oxygen demand and without reducing coronary perfusion; (2) prevent further neurohormonal activation, favorably modulate the existing neurohormonal milieu, or both; (3) be applicable in the context of known evidence-based therapies, such as ACE inhibitors and -blockers; (4) help control ventricular rate in atrial fibrillation; (5) have a formulation for intravenous use during the acute phase of heart failure and an oral formulation for long-term use; (6) importantly, improve symptoms and signs, decrease rehospitalization rate, improve survival, or all 3; and (7) be affordable for the millions of patients with heart failure throughout the world. This last point is particularly important because many patients with heart failure cannot afford newer, much more expensive drugs. Digoxin has many of these properties. It improves hemodynamics acutely, both at rest and with exercise. These hemodynamic effects are additive when digoxin is used with other vasoactive agents. Digoxin has beneficial neurohormonal actions, does not impair renal function, and has a neutral or beneficial effect on heart rate and blood pressure. The intravenous form can easily be switched to the oral form, which is taken once a day. Digoxin is inexpensive, and thera-

Digoxin for the treatment of chronic and acute heart failure syndromes

Digitalis preparations have been used for centuries. Digoxin is an agent that is readily available, can be administered acutely and long-term, intravenously or orally, is safe and may be beneficial in both acute and chronic heart failure (HF). It may be an ideal drug for the treatment of acute heart failure syndromes and warrants further investigation in large clinical trials. The role of digoxin in acute and chronic HF was discussed at the 2008 European Society of Cardiology Working Group on Acute Cardiac Care Meeting held in Versailles, France from 25-28 October 2008. This report represents a summary of the presentation at this meeting.

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

Submolecular mechanisms underlying in vitro and in vivo effect of cardiac glycosides on contractile activity of myocardial myofibrils during heart failure

The development of severe heart failure associated with toxicoallergic myocarditis is accompanied by profound structural and conformational changes in the outer domain of actin (major protein in a thin filament of cardiomyocyte sarcomere). These changes were revealed in subdomains 1 (Cys374 and Cys10) and 2 (Lys61 and Tyr69). Structural and conformational changes in the monomer and protomer of the actin thread during heart failure were energetically forbidden. Variations in the distance between amino acid residues exceeded 0.26 nm. They were partly or completely reversible in vivo under the influence of cardiotropic drug refracterin with high antihypoxic activity, as well as in vitro after treatment with digitalis preparations optimizing the concentration of ATP.

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

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. 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. 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. 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.

Psychiatric effects of drugs for other disorders

Neuropsychiatric effects account for up to 30% of adverse drug reactions and can be caused by drugs administered for physical conditions in psychiatrically normal patients. Such reactions can include anxiety, depression, psychosis, mania, delirium, sleep disorders and hallucinations. They are more common in elderly or ill patients, though a psychiatric history may increase vulnerability. The reactions are sometimes dose-related, but can occur at therapeutic doses or on drug withdrawal. Drugs used for parkinsonism, cardiovascular, endocrine and gastrointestinal disorders, pain syndromes, and bacterial, parasitic or viral infections may all cause psychiatric effects. Such drugs include dopaminergic and antimuscarinic agents, digitalis preparations, β-adrenoceptor antagonists, glucocorticoids, sex hormones, anabolic steriods, H2-receptors antagonists, protein pump inhibitors, antibiotics, antimalarials, antiviral drugs and interferons. Management may be straightforward when the cause is recognized, but patients taking several drugs need careful assessment because adverse psychiatric effects can result from drug interactions.

Treatment of Chronic Heart Failure in a Managed Care Setting

Effective therapy for chronic heart failure (CHF) is underutilized despite a broad consensus regarding treatment recommendations. As a quality improvement project designed to reduce preventable hospitalizations associated with CHF, we examined use of angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta-adrenergic receptor blockers (BB) in a population of patients enrolled in a managed care plan. Medicare and commercial enrollees were included. Patients with CHF were identified using claims data (International Classification of Disease 9th Clinical Modification code 428) covering January 1, 1998 through December 31, 1998. Drug utilization data were obtained from the plan's pharmacy benefits database. Data were available for 1220 patients. The mean age (+/- SD) was 71 +/- 12 years, 53% were female, and 84% were Medicare enrollees. Prescriptions for ACEI, ARB and BB were filled by 52%, 9% and 25% of patients, respectively. Prescriptions for diuretics, digitalis preparations, and calcium channel blockers (CCB) were filled by 69%, 34%, and 32%, respectively. Therefore, almost half of patients with CHF were not receiving ACEI therapy, even though it had been proven to reduce morbidity and mortality related to CHF. Furthermore, three-quarters of patients were not receiving BB therapy, a similarly effective therapy. In contrast, CCB and digitalis have not been convincingly shown to reduce mortality in patients with CHF broadly defined. Utilization of CCB and digitalis exceeded that of BB. Managed care organizations should develop, test, and implement network-level strategies designed to optimize the appropriate utilization of effective drug therapies for patients with CHF.

Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study.

To estimate incidence rates of drug-related hospitalizations (DRHs) in a longitudinal population-based study with prospective event assessment. Cohort study and time-trend analysis. All departments of internal medicine and emergency departments in the urban regions of Jena and Rostock, Germany, serving about 520,000 residents. All patients admitted between October 1997 and March 2000. Patients with severe cutaneous reactions were excluded. Incidence of DRH was defined by symptoms or diagnoses at admission that were very likely, likely, or possibly caused by prescription medications, according to a standardized assessment. The incidence of DRH was 9.4 admissions per 10,000 treated patients [95% confidence interval (CI) 9.0-9.9]. Rates were highest for antithrombotics with 26.9 admissions per 10,000 treated patients (95% CI 23.6, 30.1). Most frequent events were gastroduodenal lesions and bleeding (45%). Digitalis preparations showed a linearly increasing trend from 2/10,000 to 14/10,000 during ten quarters ( P<0.0001), which was exclusively attributable to digitoxin, the major source of digitalis in the study area (93%). The incidence of DRH increased with age (4/10,000 to 20/10,000). The mean length of stays in patients with DRH was 13+/-10.6 days. Cumulative direct costs for hospitalization were Euro 4 million in the two urban study areas. The annual direct costs for Germany were estimated to be Euro 400 million. DRHs are a considerable public health and economic burden. A longitudinal design can observe changes in population-based incidence over time. This approach can be used for public-health planning or to evaluate outcomes of quality management programs designed to reduce drug-induced illness.

The Diagnosis

Continued from p. 26 The first ECG reveals tachycardia at a rate of 106 beats/minute with frequent premature ventricular beats (PVCs) consistent with bigeminy (Figure 1). The second ECG reveals a marked change with increased tachycardia to 154 beats/minute and alternating wide-complex QRS morphologies consistent with bidirectional ventricular tachycardia consistent with the diagnosis of digitalis toxicity (Figure 2).Figure 1: Initial ECG demonstrates atrial fibrillation with frequent PVCs in a bigeminal pattern.Figure 2: Subsequent ECG demonstrates a bidirectional ventricular tachycardia with alternating wide-complex QRS morphologies.The cardiac glycoside medications, digoxin and digitoxin, are derived from digitalis, commonly found in several plants, including oleander, foxglove, and lily of the valley.1 Therapeutically, these medications are used primarily to slow conduction through the atrio-ventricular (AV) node (such as in atrial fibrillation or flutter) or to improve cardiac inotropy (such as in congestive heart failure). At the cellular level, digitalis preparations act by inhibiting the sodium-potassium adenosine triphosphatase (ATP-ase) pump and increasing intracellular calcium concentration. As a result, digitalis medications increase myocardial contractility. These intracellular changes also affect the conduction system, resulting in a diminished sinus node discharge rate, shortened atrial refractoriness and prolonged AV node refractoriness. The effect is largely mediated by the autonomic nervous system, enhancing vagal tone both centrally and peripherally.2 The end result is a slowing of conduction through the AV node coupled with a propensity for increased cardiac automaticity.3 The ECG interpretation of “digitalis effect” refers to changes associated with the presence of digitalis (or its derivatives) but not with clinical toxicity. Findings include the classic “scooped” ST depression, variable T-wave changes (inversion, flattening, or biphasic), prominent U-waves, QT shortening, and PR prolongation. Digitalis Toxicity Both acute and chronic toxicity can occur with digitalis medications. In acute toxicity, nausea, vomiting, and evidence of cardiotoxicity are prominent. Chronic toxicity can result in malaise, weakness, and nonspecific symptoms, though classic, rare visual disturbances (yellow halos around lights) have been described.4 ventricular ectopy from increased automaticity is often the earliest electrocardiographic finding, often manifesting as frequent PVCs (unifocal and multifocal), and can result in bigeminy (Figure 1) or trigeminy. Delayed conduction can result in a wide variety of AV conduction blocks, from first degree block to complete heart block, though Mobitz type II is considered rare.1 In addition, bradydysrhythmias can result from increased vagal tone. In patients with known atrial fibrillation who present with a slowing or regularization of their ventricular rate, it is important to consider digitalis toxicity. Toxicity can result in a regular AV nodal escape rhythm that may mimic conversion or improved rate control.1 Along with ventricular ectopy and conduction block, other classic digoxin toxicity dysrhythmias include paroxysmal atrial tachycardia (PAT) with block, junctional (AV nodal) tachycardia, and VT. With PAT with block, the atrial rate is usually 150 to 250 beats per minute, with variable AV blockade (most commonly second degree). Junctional tachycardia occurs when SA node activity is suppressed such that the AV node outpaces it. The resulting junctional escape rhythm manifests with a ventricular rate of 40 to 60 beats/minute, but accelerated rhythms are common. The occurrence VT in a patient on digoxin should raise the possibility of cardiac toxicity. Bidirectional VT and ventricular bigeminy occur when there are alternating bundle branch block patterns seen in the wide-complex QRS morphologies (Figure 2). Though rare, bidirectional VT is considered virtually pathognomonic for digitalis toxicity.4 Treatment Treatment of digitalis toxicity depends on clinical presentation, cardiovascular status and electrocardiographic manifestations. For many patients who are hemodynamically stable and present with less severe degrees of ventricular ectopy and block, temporary withdrawal of the medication may suffice. Patients with significant hemodynamic compromise require more aggressive therapy. Careful attention to correcting electrolyte abnormalities that may exacerbate digoxin-related dysrhythmias is critical. However, hyperkalemia should not be treated with calcium because doing so may worsen ventricular ectopy. Digoxin-specific Fab fragments should be considered for those patients with severe, life-threatening cardiac toxicity, hemodynamic compromise, or hyperkalemia. In general, use of Fab should not be based soley on the serum drug level. Fab rapidly reverses conduction disturbances, restores myocardial contractility, and reestablishes ATP-ase activity by binding digoxin.2 Adverse effects include worsening CHF, tachydysrhythmias and hypokalemia from reversal of therapeutic digoxin. Despite these drawbacks, the introduction of Fab has revolutionized the treatment of severe poisoning. Because of the suspicion for digoxin toxicity and his hypotension, the patient was treated with Fab and admitted to the coronary care unit. Ten hours later, the patient reported feeling improved. A repeat ECG demonstrates resolution of the ventricular ectopy (Figure 3). The patient's physician reported that he had recently increased the patient's digoxin dose from 0.125 mg to 0.250 mg per day as a response to the palpitations the patient had been experiencing.Figure 3: ECG after treatment with Fab demonstrates atrial fibrillation with no ventricular ectopy.

Predictors of unsuccessful electrical cardioversion in atrial fibrillation

R of sinus rhythm improves functional capacity and alleviates palpitations in patients with atrial fibrillation (AF). The advantages of direct-current cardioversion include the immediate restoration of sinus rhythm, as opposed to the unpredictable time to cardioversion in pharmacologic intervention, and the avoidance of potential adverse drug reactions. Although direct-current cardioversion is thought to have a higher success rate than pharmacologic intervention, it may fail to restore sinus rhythm in 5% to 30% of procedures. Few data are available regarding the association between clinical variables and the failure of direct-current cardioversion. Also, the relation between abnormalities of cardiac function and the success of direct-current cardioversion has not been studied in a large number of patients. This study assesses the success rate of direct-current cardioversion in patients with AF and the relation between clinical and echocardiographic variables and the success of direct-current cardioversion. • • • We studied 692 patients (459 men [66%] and 233 women [34%], mean age SD 67 13 years) with AF who had a first elective direct-current cardioversion at Mayo Clinic (Rochester, Minnesota). This study was approved by the Institutional Review Board of the Mayo Foundation. The duration of AF was 48 hours in 653 patients (94%) and 48 hours in 39 patients (6%). All patients underwent transthoracic echocardiography before cardioversion. Transesophageal echocardiography was performed in 201 patients (29%) before cardioversion. A history of coronary artery disease was considered present if the patient had had a previous myocardial infarction, myocardial revascularization, significant coronary artery stenosis on angiography, or typical anginal complaints. Valvular heart disease was considered present if the patient had more than mild stenosis or regurgitation of 1 cardiac valve. Idiopathic dilated cardiomyopathy was defined as left ventricular dilatation and global hypokinesia without significant coronary artery disease. The duration of AF was determined by the time of documentation of AF on the electrocardiogram or the onset of symptoms, whichever occurred earlier. Two-dimensional and M-mode imaging were performed with commercially available echocardiographic machines equipped with 2.5and 3.5-MHz phased-array transducers. M-mode echocardiography was used to measure cardiac dimensions and wall thickness. A left atrial diameter of 40 mm defined left atrial dilatation. This was considered mild for values 50 mm and marked for values 50 mm. Ejection fraction at rest was measured using a previously validated modification of the method of Quinones in Dujardin et al or by visual estimation. Structural heart disease was defined as any of the following: valvular heart disease, coronary heart disease, cardiomyopathy, or ejection fraction 50%. All procedures were performed with electrocardiographic monitoring and full equipment for cardiopulmonary resuscitation. Digitalis preparations were withheld for 24 to 48 hours before the procedure. After administration of intravenous sedation, synchronized direct-current monophasic shock was administered using the anteroposterior paddle position (sternal body angle of the left scapula). If sinus rhythm was not restored after the first shock, the procedure was repeated (up to 4 times) using a larger number of joules (up to 360 J). The number of joules with which cardioversion was initiated was determined for each patient according to physician discretion. Electrocardiography was performed before and after the procedure to verify cardiac rhythm. Successful cardioversion was defined as restoration of sinus rhythm after administration of direct-current shock. Unless specified, data are presented as mean values SD or as frequency percentages. The rank sum and chi-square tests were used to compare differences between continuous variables and proportions, respectively. Univariate and multivariate stepwise logistic regression models were used to identify individual and joint predictors of unsuccessful cardioversion. Analyses of success were done using both the patient and the individual shock as the unit of observation to harvest information when multiple shocks were needed. Differences were considered significant if the null hypothesis could be rejected at the 0.05 probability level. These diseases were present in the study population: systemic hypertension in 355 patients (51%), coronary artery disease in 233 patients (34%), valvular heart disease in 227 patients (33%), and cardiomyopathy (idiopathic dilated, restrictive, or hypertrophic) in 125 patients (18%). Cardioversion was successful in 592 patients (86%) and unsuccessful in 100 (14%). The mean number of shocks was 2.1 1.2/patient. The mean number of joules was 222 100. In 74 patients, 50 J was used initially, with success achieved From the Division of Cardiovascular Diseases and Internal Medicine and the Section of Biostatistics, Mayo Clinic, Rochester, Minnesota. Dr. Khandheria’s address is: Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Manuscript received June 13, 2001; revised manuscript received and accepted September 6, 2001.

Digitalis.

Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the alpha-subunit of sarcolemmal Na+K+-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.

Drugs and colon cancer.

In a case-control study of colon cancer conducted in three geographic regions of the United States, 1993 case subjects and 2410 control subjects were interviewed. In addition to queries regarding other known or suspected risk factors, subjects were asked about their use of eight drugs or drug groups. Two of these, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), have been inversely associated with risk in other studies. Three others--asthma medications, digitalis preparations, and phenmetrazine--were positively associated and the last three--diazepam, penicillin, and phenformin--were negatively associated with risk of colon cancer in an earlier study that screened pharmaceuticals for possible carcinogenic effects. Reported use of aspirin and NSAIDs were both inversely related to risk with essentially the same odds ratios (0.7, 95% confidence interval 0.6-0.8) for both drugs in both univariate and multivariate analyses controlling for use of each other and for other colon cancer risk factors. Subdivision by age at starting the drug, duration of use, latency interval, sex, race, family history of colon cancer, or proximal versus distal cancer revealed no substantial differences among subgroups for either aspirin or NSAIDs, but reduced risk was associated primarily with recent aspirin use. Phenformin showed a strong positive association but the data concerning this drug appeared to be inaccurate. The other drugs and drug groups showed essentially no association with colon cancer risk.

Does Digoxin Provide Additional Hemodynamic and Autonomic Benefit at Higher Doses in Patients With Mild to Moderate Heart Failure and Normal Sinus Rhythm?

Objectives. This study sought to examine the hemodynamic and autonomic dose response to digoxin.Background. Previous studies have demonstrated an increase in contractility and heart rate variability with digitalis preparations. However, little is known about the dose-response to digoxin, which has a narrow therapeutic window.Methods. Nineteen patients with moderate heart failure and a left ventricular ejection fraction <0.45 were studied hemodynamically using echocardiography and blood pressure at baseline and after 2 weeks of low dose (0.125 mg daily) and 2 weeks of moderate dose digoxin (0.25 mg daily). Loading conditions were altered with nitroprusside at each study. Autonomic function was studied by assessing heart rate variability on 24-h Holter monitoring and plasma norepinephrine levels during supine rest.Results. Low dose digoxin provided a significant increase in ventricular performance, but no further increase was seen with the moderate dose. Low dose digoxin reduced heart rate and increased heart rate variability. Moderate dose digoxin produced no additional increase in heart rate variability or reduction in sympathetic activity, as manifested by heart rate, plasma norepinephrine or low frequency/high frequency power ratio. In addition, we did not find that either low or moderate dose digoxin increased parasympathetic activity.Conclusions. We conclude that moderate dose digoxin provides no additional hemodynamic or autonomic benefit for patients with mild to moderate heart failure over low dose digoxin. Because higher doses of digoxin may predispose to arrhythmogenesis, lower dose digoxin should be considered in patients with mild to moderate heart failure.(J Am Coll Cardiol 1997;29:1206–13)