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Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na(+)/K(+)-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.

The cardiac glycosides are a group of compounds isolated from plants and some animals. They have been used in therapy for heart failure for many years. The cytotoxic effect of many cardiac glycosides has been demonstrated, but the mechanism of action is very complicated and complex, and Na+/K+-ATPase surely plays a crucial role in it. On the other hand, Na+/K+-ATPase is regulated by many endogenous factors, such as hormones or FXYD proteins, whose role in regulating the cell cycle has been studied intensively. This review focuses on the role of Na+/K+-ATPase in regulating the cell growth, the cell cycle and the cell proliferation and on the involvement of cardiac glycosides in regulating Na+/K+-ATPase. The cytotoxic effect of cardiac glycosides is discussed with respect to the apoptotic mechanisms possibly induced by these compounds. Novel strategies in cancer therapy based on cardiac glycosides are discussed as are possibilities for counteracting multidrug resistance by using cardiac glycosides. The aim of this review is to present cardiac glycosides not only as pharmaceuticals used in the management of heart failure, but also as potent cytotoxic agents with potential uses in cancer treatment.

Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K(+) and increase of Na(+) and Ca(2+); intracellular acidification; inhibition of IL-8 production and of the TNF-α/NF-κB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment.

Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoïkis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To (1) measure utilization of and adherence to heart failure medications and (2) assess whether better adherence is associated with lower Medicare spending., Study Design: Pooled cross-sectional design using six 3-year cohorts of Medicare beneficiaries with congestive heart failure (CHF) from 1997 through 2005 (N = 2204)., Methods: Adherence to treatment was measured using average daily pill counts. Bivariate and multivariate methods were used to examine the relationship between medication adherence and Medicare spending. Multivariate analyses included extensive variables to control for confounding, including healthy adherer bias., Results: Approximately 58% of the cohort were taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), 72% a diuretic, 37% a beta-blocker, and 34% a cardiac glycoside. Unadjusted results showed that a 10% increase in average daily pill count for ACE inhibitors or ARBs, beta-blockers, diuretics, or cardiac glycosides was associated with reductions in Medicare spending of $508 (not significant [NS]), $608 (NS), $250 (NS), and $1244 (P <.05), respectively. Estimated adjusted marginal effects of a 10% increase in daily pill counts for beta-blockers and cardiac glycosides were reductions in cumulative 3-year Medicare spending of $510 to $561 and $750 to $923, respectively (P <.05)., Conclusions: Higher levels of medication adherence among Medicare beneficiaries with CHF were associated with lower cumulative Medicare spending over 3 years, with savings generally exceeding the costs of the drugs in question.

Cardiovascular drugs are used in pregnancy to treat maternal and fetal conditions. Mothers may also require drug therapy postpartum. Most cardiovascular drugs taken by pregnant women can cross the placenta and therefore expose the developing embryo and fetus to their pharmacologic and teratogenic effects. These effects are influenced by the intrinsic pharmacokinetic properties of a given drug and by the complex physiologic changes occurring during pregnancy. Many drugs are also transferred into human milk with potential adverse effects on the nursing infant. This article summarizes some of the literature concerning the risks and benefits of using cardiovascular drugs during pregnancy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the inhibition of the plasma membrane Na(+)- and K(+)-dependent adenosine triphosphatase (Na(+)/K(+)-ATPase). CGs exacerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate syngeneic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.

A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na(+)/K(+)-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.

The principal active constituent of the botanical drug candidate PBI-05204, a supercritical CO(2) extract of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clinical trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 extract can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that additional, non-cardiac glycoside components of PBI-05204 may also contribute to the observed neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clinical potential for PBI-05204 in the treatment of ischemic stroke and prevention of associated neuronal death., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Objectives: RECORDAF is the first worldwide, prospective, observational survey of management of atrial fibrillation (AF) in unselected, community-based patients., Background: Primary outcomes were therapeutic success and clinical outcomes associated with rhythm-control and rate-control strategies., Methods: Patients with recent-onset AF were included (n = 5,604). Treatment strategy (rhythm control or rate control) was noted at baseline. Follow-up was 12 months. Therapeutic success required that strategy was unchanged without clinical events. Further maintenance of sinus rhythm was required in the rhythm-control group, and heart rate ≤80 beats/min in the rate-control group., Results: Data from 5,171 patients were assessable. Therapeutic success was 54% overall (rhythm control 60% vs. rate control 47%), a result driven by control of AF: rhythm control, 81% vs. rate control, 74%. After adjustment for propensity score quintiles, the rhythm-control strategy was significantly related to superior therapeutic success (odds ratio: 1.34, 95% confidence interval: 1.15 to 1.55; p = 0.0002). Clinical events occurred in 18% of patients. The arrhythmia management strategy was not predictive of clinical events. The type (persistent), presence at baseline visit, and duration (>3 months) of AF, together with age older than 75 years and the presence of heart failure, predicted progression to permanent AF. The choice of rhythm control reduced the likelihood of AF progression (odds ratio: 0.20, 95% confidence interval: 0.17 to 0.25; p < 0.0001)., Conclusions: Clinical outcomes in AF patients were driven mainly by hospitalizations for arrhythmia/proarrhythmia and other cardiovascular causes, but not by the choice of rate or rhythm strategy. Rhythm-control patients progressed less rapidly to permanent AF., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiac glycosides, statins, β-blockers, angiotensin-I converting enzyme inhibitors (ACEIs), and angiotensin II type 1 receptor blockers (ARBs) are widely used cardiovascular medications with pleiotropic properties. Many of these medications have been investigated in other diseases, including cancer. Cardiac glycosides and statins have advanced to clinical trial testing in cancer therapeutics, with variable success. Early observations in breast cancer were consistent with a more benign histologic phenotype among women taking digitalis compared to their counterparts who did not receive cardiac glycosides. Cardiac glycosides can induce apoptosis in cancer cells through various mechanisms and sensitize them to the effects of antitumor therapy. By blocking the generation of prenyl units, statins impair prenylation, an important posttranslational modification of proteins whose function depends on membrane anchoring. Statins also impair protein folding and N-glycosylation and inhibit the upregulation of cholesterol synthesis associated with chemotherapy resistance. Stress and catecholamine release promote tumor growth and angiogenesis, effects that can be mitigated by β-blockers. Components of the renin-angiotensin-aldosterone system are expressed in various cancers and are involved in carcinogenesis and tumor progression. Angiotensin II has potent mitogenic and angiogenic properties that can be blocked with ACEIs and ARBs. Although it is unclear whether the promising preclinical activity of many cardiovascular medications has clinically meaningful implications beyond the benefit in cardiovascular morbidity and mortality, the prevention or improvement of prognosis of common malignancies with medications known to reduce cardiovascular morbidity and mortality is encouraging and deserves further clinical investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results., Principal Findings: In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC(50) values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC(50) was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines., Conclusion: It is suggested that further investigation regarding CGs may be focused on diagnoses like T- and B-precursor ALL.

The data on the prevalence of chronic obstructive pulmonary disease (COPD), its possible complications and outcomes are presented with reference to current concepts of this pathology and personal experience of the author with diagnostics and treatment of cardiac insufficiency in patients with COPD. A rationale for the use of selected pharmaceutical products and their combinations for the treatment of COPD is proposed.

Scientific research has proved that coagulation system is more active in patients with chronic heart failure than in healthy people. Therefore, the aim of this article was to review the data in literature about changes in coagulation system after treatment of chronic heart failure with β-adrenoblockers, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, cardiac glycosides, diuretics, anticoagulants, and antiagregants. It is known that β-adrenoblockers used separately decrease platelet aggregation and angiotensin-converting enzyme inhibitors reduce P-selectin expression as well. Low-molecular-weight heparin decreases the concentrations of prothrombin fragments, D-dimers; orally administered anticoagulants reduce the concentrations of interleukin 6, von Willebrand factor, intercellular adhesion molecules, fibrinogen 1+2 and increases the concentration of plasminogen activator inhibitor-1. Both anticoagulants reduce the levels of VII:C factors and thrombin-antithrombin III complex. The use of aspirin together with clopidogrel reduces the concentration of intercellular adhesion and platelet-endothelial cell adhesion molecules and expression of P-selectins; however, these concentrations do not vary while using aspirin alone. The treatment with ACE inhibitors together with calcium antagonists and β-adrenoblockers decreases activated partial thromboplastin time, concentrations of D-dimers, plasminogen activator inhibitor-1, vascular cell adhesion molecules, CD63 and expression of L- and P-selectins. While analyzing the effect of abovementioned agents, it is necessary to mention that data reported by different authors are not consistent. Therefore, the effect of particular drugs on the particular parameters of coagulation system has not been completely elucidated.

The pharmacodynamics and pharmacokinetics of medications, their therapeutic and toxic effects are age dependant. In the treatment of old people polypharmacy is widely used. The most common results of polypharmacy are increased adverse drug reactions, drug-drug interactions. In this study the use of different medications at the Departments of General Medicine and Cardiology (Tbilisi Republic Hospital) was analyzed. The case histories (1995, 2000 and 2005) of 1708 patients were studied. It was found that in 2005 the number of 60 years and older patients has doubled comparably with 1995, but the number of 24-44 years old patients remained almost the same. The complication rate was higher in elderly as compared with younger patients. It was found that in treatment of elderly population hypotensive drugs, diuretics and cardiac glycosides are used excessively. In the case of excess use of antihypertension medications there is a big risk of developing arterial hypotension. In old people it may lead to orthostatic hypotension, in youth - to dizziness. The frequent use of diuretics in old people may be accompanied with dehydration and risk of developing thromb formation. Hyponatraemia, hypokalaemia, hypomagnesemia lead to heart rhythm disturbances and risk of glycoside intoxication. In old people the therapeutical doses of diuretics depend not only on their biological activity, but also on the ability of their absorption from the gastrointestinal tract, on the organism's resistance and in the case of repeated intake on their cumulation quality and extraction.

The REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation (RecordAF) is the first worldwide, 1-year observational, longitudinal study of the management of paroxysmal/persistent atrial fibrillation (AF) in recently diagnosed patients. The study was conducted at 532 sites in 21 countries across Europe, America, and Asia; recruitment was completed in April 2008. The primary objectives were to prospectively assess the therapeutic success and clinical outcomes in rhythm- and rate-control strategies. The study design and patient baseline data are reported. A total of 5,814 patients with AF were registered, and 5,604 were eligible for evaluation. Rhythm- and rate-control strategies were applied to 55% and 45% of patients, respectively, at study inclusion. Rhythm-control patients mainly received class III agents (45%) or beta blockers (51%), except for sotalol, and rate-control patients mainly received beta blockers (72%), except for sotalol, or cardiac glycosides (34%). Patients receiving a rhythm-control strategy were younger, had a lower resting heart rate, were more frequently symptomatic, and were more likely to have recently diagnosed AF or paroxysmal AF compared to patients receiving a rate-control strategy. A rate-control strategy was more common in patients with a history of heart failure or valvular heart disease and persistent AF. Rate-control patients more often had previous electrocardiographic evidence of AF and were not in sinus rhythm at inclusion (p <0.01 for both end points). Patients were followed at 6 and 12 months, and changes in therapeutic strategy and clinical outcomes were recorded. In conclusion, the RecordAF study results will provide a global perspective on current AF treatment strategies., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation (RecordAF) study is the first worldwide, prospective, survey of real-life management of atrial fibrillation (AF) in recently diagnosed patients (n = 5604) with a 1-year follow-up., Hypothesis: Surveys of AF management have identified a divergence between guidelines and clinical practice, and an overinterpretation of guidelines in low-risk patients., Methods: : Physicians' theoretical approaches to rhythm and rate control were investigated using a pre-study questionnaire., Results: One cardiologist, from each of the 583 sites in 6 regions, completed a questionnaire on their practice and management of AF patients. In AF patients with structural heart disease (SHD), amiodarone was the most frequent choice of first-line rhythm control agents in all regions. Amiodarone or sotalol tended to be the preferred second-line rhythm control agents, 1 exception being Central/South America. beta-Blockers were the first-line rate control agents for patients with AF and SHD in all regions, and calcium channel blockers and cardiac glycosides were the most common second-line rate control treatments in all regions, except Asia. In lone AF patients, propafenone (30.6%), flecainide (24.1%), and amiodarone (21.7%) were the most common global choices of first-line rhythm control, and amiodarone or sotalol were the preferred second-line rhythm control agents, 1 exception being Central/South America., Conclusions: These results highlight points of divergence from the American College of Cardiology (ACC)/ American Heart Association (AHA)/European Society of Cardiology (ESC) guidelines for the management of AF in terms of first-line drug selection in patients with associated SHD or coronary artery disease., (Copyright (c) 2010 Wiley Periodicals, Inc.)

Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca(2+)-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1alpha (HIF-1alpha) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor growth via the inhibition of HIF-1alpha synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1alpha and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.

Despite significant progress in oncology therapeutics in the last decades, the urge to discover and to develop new, alternative or synergistic anti-cancer agents still remains. For centuries it has been known that the coarse shrub Calotropis procera is a very promising source of ascaricidal, schizonticidal, anti-bacterial, anthelmintic, insecticidal, anti-inflammatory, anti-diarrhoeal, larvicidal and cytotoxic chemicals. Different compounds like norditerpenic esters, organic carbonates, the cysteine protease procerain, alkaloids, flavonoids, sterols as well as numerous types of cardenolides have provided this plant for centuries with scientists' interest. The chemical class of cardenolides and their related bioactivity evaluation and structure-activity relationship (SAR) studies pointed out their therapeutic utility and led to the discovery of promising drug candidates. Recently the cardiotonic steroid UNBS1450 01 (derived from 2-oxovoruscharin 02) from C. procera was shown to additionally exert an anti-cancer activity. UNBS1450 01 has been proven to be a potent sodium pump inhibitor, showing anti-proliferative and cell death-inducing activities. This anti-cancer potential of UNBS1450 01 is achieved by disorganization of the actin cytoskeleton after binding to the sodium pump at the cellular membrane, by inducing autophagy-related cell death, by repressing NF-kappaB activation as well as by down-regulating c-Myc in cancer cells. We aim to review pharmacologically important chemical extracts from C. procera and focus more specifically on the anti-cancer activities of UNBS1450 01.

Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, have been postulated to play important roles in health and disease for nearly half a century. Recent discoveries, which include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of an alternative mechanism by which CTS can signal through the Na(+)/K(+)-ATPase, have increased the interest in this field substantially. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the regulation of cell growth, differentiation, apoptosis, and fibrosis, the modulation of immunity and of carbohydrate metabolism, and the control of various central nervous functions and even behavior. This review focuses on the physiological interactions between CTS and other regulatory systems that may be important in the pathophysiology of essential hypertension, preeclampsia, end-stage renal disease, congestive heart failure, and diabetes mellitus. Based on our increasing understanding of the regulation of CTS as well as the molecular mechanisms of these hormone increases, we also discuss potential therapeutic strategies.

Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for the treatment of heart failure and atrial arrhythmia, and the mechanism of their positive inotropic effect is well characterized. Exciting recent findings have suggested additional signalling modes of action of Na+/K+-ATPase, implicating cardiac glycosides in the regulation of several important cellular processes and highlighting potential new therapeutic roles for these compounds in various diseases. Perhaps most notably, the increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.

Purpose: To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK alpha1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues., Design: The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity,and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration., Results: The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2"-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK alpha subunits (including alpha1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK alpha1 over-expressing glioma cells., Conclusions: Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha1 subunit.

The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past five years have revealed these compounds to be involved in complex cell-signal transduction mechanisms, resulting in selective control of human tumor but not normal cellular proliferation. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies of their anticancer potential as single or adjuvant treatments may provide insight into these potentially valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been overlooked in the past.

Leterature data and own investigations are summarized in the article. New experimental facts about mechanism of action of cardiac glycosides (especially digoxin) were obtained last year. It was shown that in human organism there are endogenous cardiosteroids (digitalis-like substances, endogenous oubain and other). They are in different organs (adrenal glands, hypothalamus, pituitary gland) and have influence on different organs and systems. Indications, contraindications, side effects, interactions with other drugs have been studied by cardiologists. Results of international multicentere studies demonstrate high efficacy of digoxin in treatment of chronic heart failure caused by compromised contractile activity of myocardium, atrium fibrillation and is used for controlling number of heart contractions and supraventricular paroxysmal tachycardia. More than 200 years history of scientific researches and clinical use of cardiac glycosides show that this group of medicine may be applied in a combine pharmacotherapy of chronic heart failure together with antihypertensive drugs.

The sodium pump, Na(+)/K(+)-ATPase, could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules.

Cardiotonic steroids (CTS), long used to treat heart failure, are endogenously produced in mammals. Among them are the hydrophilic cardenolide ouabain and the more hydrophobic cardenolide digoxin, as well as the bufadienolides marinobufagenin and telecinobufagin. The physiological effects of endogenous ouabain on blood pressure and cardiac activity are consistent with the "Na(+)-lag" hypothesis. This hypothesis assumes that, in cardiac and arterial myocytes, a CTS-induced local increase of Na(+) concentration due to inhibition of Na(+)/K(+)-ATPase leads to an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) via a backward-running Na(+)/Ca(2+) exchanger. The increase in [Ca(2+)](i) then activates muscle contraction. The Na(+)-lag hypothesis may best explain short-term and inotropic actions of CTS. Yet all data on the CTS-induced alteration of gene expression are consistent with another hypothesis, based on the Na(+)/K(+)-ATPase "signalosome," that describes the interaction of cardiac glycosides with the Na(+) pump as machinery activating various signaling pathways via intramembrane and cytosolic protein-protein interactions. These pathways, which may be activated simultaneously or selectively, elevate [Ca(2+)](i), activate Src and the ERK1/2 kinase pathways, and activate phosphoinositide 3-kinase and protein kinase B (Akt), NF-kappaB, and reactive oxygen species. A recent development indicates that new pharmaceuticals with antihypertensive and anticancer activities may be found among CTS and their derivatives: the antihypertensive rostafuroxin suppresses Na(+) resorption and the Src-epidermal growth factor receptor-ERK pathway in kidney tubule cells. It may be the parent compound of a new principle of antihypertensive therapy. Bufalin and oleandrin or the cardenolide analog UNBS-1450 block tumor cell proliferation and induce apoptosis at low concentrations in tumors with constitutive activation of NF-kappaB.

Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body's K(+) content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca(2+) influx via the Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-kappaB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy. In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive alpha(1) isoform of Na(+)/K(+)-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.

We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.

Introduction: Plantain, a herbal remedy, has been reported to interfere with therapeutic drug monitoring of digoxin. We evaluated three commercially available plantain products for potential interference with therapeutic drug monitoring of digoxin and 13 other common drugs., Method: Dry content of plantain capsule or plantain leaf was extracted with either methanol or ethanol:water (60:40 by volume), added to drug-free serum and apparent digoxin was measured by both fluorescence polarization immunoassay and microparticle enzyme immunoassay. Using immunoassays, we also measured apparent concentrations of 13 other drugs (tobramycin, procainamide, tricyclic antidepressants, quinidine, carbamazepine, phenytoin, theophylline, valproic acid, amikacin, gentamycin, phenobarbital, salicylate and acetaminophen [paracetamol]) due to the presence of plantain. In separate experiments, a serum pool prepared from patients receiving digoxin was further supplemented with plantain and observed digoxin values were compared with original digoxin concentration. The presence of any cardiac glycoside in plantain was also investigated using thin layer chromatography (TLC)., Results: We observed no apparent digoxin in the presence of plantain in serum. Moreover, when aliquots of digoxin serum pool were supplemented with various amounts of plantain, the observed digoxin concentrations in the presence of plantain compared well with original digoxin concentration. TLC analysis did not show the presence of either digoxin or digitoxin in plantain products studied. Moreover, plantain did not affect immunoassay results of the 13 other drugs studied., Conclusions: The plantain products studied did not interfere with therapeutic drug monitoring of digoxin as well as 13 other commonly monitored drugs.

Objective: To investigate the effectiveness and safety of various agents on paroxysmal atrial fibrillation in the elderly over 75 years old., Methods: Totally 264 in-patients (75-91 years old, 185 males and 79 females) with atrial fibrillation history of less than 7 days were enrolled in this study. A total of 611 atrial fibrillation episodes were recorded, but 130 episodes (22.3%) of atrial fibrillation were auto-converted to sinus rhythm. The rest 481 episodes of atrial fibrillation were divided into six groups based on the drug used., Results: The cardioversion ratio of atrial fibrillation were 9.5%, 46.9%, 71.7%, 55.9%, 32.7%, and 73.6% in control, cedilanid, amiodarone, propafenone, verapamil, and quinidine groups, respectively. Ventricular rate control were 5.4%, 83.6%, 84.9%, 77.9%, 78.8%, and 11.3% in those groups, respectively. The total effective rates of amiodarone and cedilanid groups were the highest. When the ventricular rate was controlled to below 90 bpm, the patients would almost complain of no discomfort. No severe side-effect was observed in each group., Conclusion: Amiodarone and cedilanid may be the proper drugs for the treatment of paroxysmal atrial fibrillation in the elderly. The above antiarrhythmics in each therapeutic group were relatively safe and effective.

The well known and accepted mode of action of cardiac glycosides is inhibition of the ubiquitous plasma membrane Na+, K+-ATPase that leads to increased intracellular Ca2+ ion concentrations. Ca2+ ions play pivotal role in many signaling pathways including those regulating apoptosis. It has been suggested that some forms of cardiac glycosides inhibit proliferation and induce apoptosis in prostate cancer cells in clinically relevant concentrations. It was also found out that the degree to which cardiac glycosides inhibited cancer cell growth was correlated to topoisomerase II-inhibiting activity. Digitoxin at concentrations found in cardiac patients induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Cardiac glycosides can also regulate one of the most potent angiogenesis promoting substances, fibroblast growth factor-2 (FGF-2), and may inhibit activation of the transcription factor NF-kappaB. FGF-2 and NF-kappaB are relevant targets for anticancer drugs. There is growing interest in evaluating the oleander products and possibly other cardiac glycosides as antineoplastic agents. The first of these therapies to be developed in the United States is a patented, water-soluble oleander extract called Anvirzel.

Chronic heart failure (CHF) is a leading cause of hospitalization and is associated with a poor prognosis, although in the past decade substantial progress has been made in understanding the pathophysiology and therapy of CHF with reduced left ventricular (LV) ejection fraction. Use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor antagonists either individually or in combination, certain beta-receptor blockers, and judicious use of aldosterone antagonists, has reduced hospital admission rates and mortality from CHF with reduced LV ejection fraction. More clinical trials are needed, however, particularly in patients with CHF and preserved LV ejection fraction. In patients who remain symptomatic despite medical therapy, and who have long QRS intervals (>0.12 s) and markedly reduced LV ejection fraction, the value of cardiac resynchronization therapy with a biventricular pacemaker has now been demonstrated. Yet, morbidity and mortality remain high, indicating a major need for further improvement. Novel therapies include medical management with statins, vasopressin antagonists, erythropoietin, oxypurinol and levosimendan, which improve vascular and myocardial function and reduce fluid overload, in addition to surgical approaches, which reduce LV remodeling. These routes might not, however, suffice in patients with CHF and LV dysfunction. Prevention of apoptosis and particularly regeneration of cardiac muscle would represent a shift of the current paradigm. Stem-cell-based therapies are rapidly evolving, and while basic science is needed to optimize these strategies, medium-sized clinical studies could help to verify the beneficial effects on LV function. In this review, we discuss current treatment methods and new strategies to improve treatment of CHF.

For more than 200 years, cardiotonic glycosides have been used for the treatment of congestive heart failure. Ouabain is a well-known arrow poison obtained from different Acokanthera or Strophanthus species. Much information has now accumulated that this plant toxin and its congeners are mammalian steroid hormones involved in the pathophysiology of cardiovascular diseases. There is an interesting fact that 50% patients with essential hypertension have elevated levels of endogenous ouabain. A better knowledge of the interactions of these compounds with the hormones of salt and water metabolism might help to improve the diagnosis and therapy of hypertension.

Aims: The impact on outcome of the implementation of European guidelines for the treatment of chronic heart failure (CHF) has not been evaluated. We investigated the consequences of adherence to care by cardiologists on the rate of CHF and cardiovascular (CV) hospitalizations and time to CV hospitalization., Methods and Results: We constructed class adherence indicators for angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, spironolactone, diuretics, and cardiac glycosides and GAIs (GAI3 adherence to first three classes of heart failure medication, GAI5 adherence to five classes). In the study, 1410 evaluable patients (mean age 69, 69% males, New York Heart Association (NYHA) II: 64%, III: 34%, IV: 2%) were enrolled and followed up for 6 months by 150 randomly selected cardiologists/cardiology departments from six European countries (France, Germany, Italy, The Netherlands, Spain, and UK). Overall, adherence to treatment guidelines was 60 (GAI3) and 63% (GAI5) and was better for ACE-I (88%) or diuretics (82%) than for cardiac glycosides (52%), beta-blockers (58%), and spironolactone (36%). In the three tertiles of the population defined by a decreasing mean adherence score value, CHF and CV hospitalization rates were, respectively, 6.7, 9.7, and 14.7% and 11.2, 15.9, and 20.6% (P<0.002 and P<0.001, respectively). Global adherence indicator GAI3 was an independent predictor of time to CV hospitalization in a multi-variable model together with NYHA Class, history of CHF hospitalization, ischaemic aetiology, diabetes mellitus, and hypertension., Conclusion: We demonstrate that adherence of physicians to treatment guidelines is a strong predictor of fewer CV hospitalizations in actual practice. There is a need to develop further quality improvement programmes in this condition.

Background: The medical management of heart failure (HF) in clinical practice varies considerably by country and by medical specialty., Aim: To assess the treatment of HF patients admitted to Internal Medicine departments, and to evaluate out-patient management prior to admission, by specialty., Design: Prospective cross-sectional multi-centre survey., Methods: Of 55 randomly selected Spanish hospitals, 51 agreed to participate. All patients (n = 2145) consecutively admitted for decompensated HF to the Departments of Internal Medicine of these hospitals, over 5 months, were included. Twenty variables were analysed, including aspects relating to out-patient management prior to admission., Results: Mean +/- SD age was 77.2 +/- 10.5 years, 57.3% were female, 47% had systolic dysfunction. Prescriptions at discharge: loop diuretics 85.6%, spironolactone 29.8%, ACEIs 65.8%, beta-blockers 8.7%, cardiac glycosides 39%. At admission, 86% already had a diagnosis of HF. Of these, 53% (older patients and more women) were being treated on an out-patient basis by primary care physicians. Primary care physicians requested fewer echocardiograms than internists (38% vs. 69%, p<0.001) and prescribed fewer drugs (ACEIs 40% vs. 54%, p<0.001; spironolactone 15% vs. 23%, p<0.05; beta-blockers 6% vs. 13%, p<0.01). The internists treated more incapacitated patients than the cardiologists (p<0.001), prescribed more high-dose ACEIs (20% vs. 13%, p<0.01) and spironolactone (26% vs. 20%, p<0.05), and fewer anticoagulants (32% vs. 39%, p<0.05)., Discussion: Patients admitted to medical departments with HF are different to those found in clinical trials. Their management is currently suboptimal. Differences in treatment between internists and cardiologists appear to be accounted for by differences in the patients they treat.

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Part 1 is devoted to clinical pharmacology of glycosides with special emphasis on digoxin. In low doses digoxin produces no substantial effect on contractility of left ventricular myocardium but can cause worsening of its diastolic function. Favorable action of digoxin on clinical course and outcomes of chronic heart failure is most probably related to modulation of neuro-humoral systems. Data on factors influencing sensitivity to glycosides in various categories of patients with heart failure, their interaction with other drugs, and contraindications for digoxin are also presented.

The authors of the article studied potential of various drug combinations (atenolol + enalapril + indapamide, and celanid + enalapril + indapamide) in complex treatment of patients with heart failure (HF) and supraventricular arrhythmias. The subjects were 106 patients, of whom 74 had coronary heart disease, of whom 51 had old myocardial infarction, and 18 had undergone coronary artery bypass grafting. Dilatation cardiomyopathy was found in 8, aortomitral valvular disease--in 18, and combined mitral valvular disease--in 6 patients. 36 subjects had permanent atrial fibrillation, 48--a paroxysmal form of ciliary arrhythmia, 22--paroxysms of atrial tachycardia. NYHA functional class (FC) II HF was diagnosed in 64 patients, NYHA FC III HF--in 42 patients. According to what treatment regimen was applied, the patients were divided into two groups, comparable in the main clinical and functional characteristics. Two-month therapy resulted in improvement of hemodynamics, increase of activity tolerance and improvement of life quality in both groups. The combination celanide + enalapril + indapamide in individual doses was effective in FC II-III HF with supraventricular arrhythmias. The cost of treatment with celanid is lower.

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Data obtained in prospective placebo controlled trial DIG show that digoxin significantly increases mortality of all patients with sinus rhythm and intact left ventricular systolic function (ejection fraction > 45%) and of women with left ventricular systolic dysfunction (ejection fraction < or = 45%). Men with left ventricular systolic dysfunction represent the only category of patients with chronic heart failure in sinus rhythm in whom long term administration of digoxin is justified. Digoxin does not affect mortality of these patients however it reduces requirements in hospitalizations due to worsening of heart failure.

Atrial fibrillation (AF) is the most common chronic arrhythmia. Incidence of AF in the heart failure population is high--10% to 30%--and is associated with a reduction in exercise capacity and a poor long-term prognosis. Management of AF includes 4 strategies: control of heart rate, termination of AF/conversion back to sinus rhythm, prevention of recurrences, and prevention of thromboembolic events. This article reviews these management strategies in the heart failure population.

When managing the risk factors of coronary heart diseases, therapies using drugs play an important role. This present study analyses self-reported data on current drug usage of men and women with coronary heart disease. The data were collected as a part of a wider drug utilisation survey which in turn is a module of the German National Health Interview and Examination Survey 1998 (Bundes-Gesundheitssurvey 1998). This survey was compiled by conducting a standardised computer-assisted medical interview with a representative sample of the German population between the ages of 18 and 79 years. Of the 7099 participants, 209 of the women and 252 of the men affirmed having had a medically diagnosed coronary heart disease (CHD) such as angina pectoris and/ or myocardial infarction. Slightly more men (87.3%) were using drugs to treat CHDs than the women (86.1%). They (the men) also used more drugs on average (men 3.3, women 3.0). These differences however were not statistically significant. Clear and statistically significant differences were present in the usage of salicylic acid (men 54.4%, women 45.6%), HMG CoA reductase inhibitors (men 26%, women 15.3%) and cardiac glycosides (men 14%, women 25.8%). The higher usage prevalence rate of salicylic acid found in the men still remained after taking their age, social status and the region (east vs west) into account. The differences in the usage of specific drugs in the treatment of CHDs in men and women indicate a difference in prescription behaviour in the ambulatory medical care. Whether and to which extent gender-specific differences still remain today has to be decided by using current epidemiological data representative of the population.

Cardiovascular drugs are often used in pregnancy for the treatment of maternal and fetal conditions. Mothers could also require continued postpartum drug therapy. Most cardiovascular drugs taken by pregnant women can cross the placenta and therefore expose the developing embryo and fetus to their pharmacologic and teratogenic effects. These effects are influenced by the intrinsic pharmacokinetic properties of a given drug as well as by the complex physiological changes occurring during pregnancy. Many drugs are also transferred into human milk and therefore can potentially have adverse effects on the nursing infant. This 2-part article summarizes some of the available literature concerning the risks and benefits of using various cardiovascular drugs and drug classes during pregnancy and lactation. Included in the discussion are cardiac glycosides, antiarrhythmic drugs, drugs used to treat both acute and chronic hypertension, cholesterol-lowering agents, anticoagulants, thrombolytics, and antiplatelet drugs., (Copyright 2004 Lippincott Williams and Wilkins)

Background: Despite the fact that heart failure constitutes a major health problem there are only limited data regarding pharmacotherapy along with characterization and prognosis of heart failure in the community., Aim: The aim of this study was to investigate treatment pattern in ambulatory patients with heart failure., Methods: The study is a cross-country epidemiological survey, based on registration, by 417 participating physicians, 50 consecutive ambulatory patients aged >/=65 years seeking medical care for any cause., Results: From a total of 19,877 individuals, 10,579 patients (3901 men and 6678 women, 53% of total) were diagnosed with HF. Therapy with angiotensin converting enzyme inhibitors was recommended in 68%, long acting nitrates in 62%, diuretics in 55%, cardiac glycosides in 31%, Ca blockers in 29% and beta blockers in 22% of all individuals with HF. The prevalence of particular groups of drugs administered in both genders was similar with the exception for calcium blockers, which were more frequently used in women (p<0.001), whereas long acting nitrates in men (p<0.001). In general, angiotensin converting enzyme inhibitors, long acting nitrates and cardiac glycosides use increased with age. On the contrary, beta blockers and calcium blockers were given mostly to younger patients. The most sick patients were more likely to receive angiotensin converting enzyme inhibitors, cardiac glycosides, long acting nitrates and diuretics, whereas less frequently beta blockers and calcium blockers. Combination therapy was used relatively rarely, with lowest percentage in NYHA IV., Conclusion: Compared to the other population studies, both angiotensin converting enzyme inhibitors and beta blockers were used relatively more frequently, although in the absolute terms the latter was clearly underused. The high rate of Ca blockers prescription is a matter of concern. More attention should be paid to optimising combination usage and introducing beta blockers early in all stable patients.