Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na⁺/K⁺-ATPase.

In 1972 Neal Bricker presented the "trade-off" hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990's Xie and Askari published seminal studies indicating that the Na⁺/K⁺-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term "trade-offs" of the physiological adaptation processes which Bricker originally proposed in the 1970's. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this "trade-off" with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

Cardiac glycosides use and the risk and mortality of cancer; systematic review and meta-analysis of observational studies.

BACKGROUND: Cardiac glycosides (CGs) including digitalis, digoxin and digitoxin are used in the treatment of congestive heart failure and atrial fibrillation. Pre-clinical studies have investigated the anti-neoplastic properties of CGs since 1960s. Epidemiological studies concerning the association between CGs use and cancer risk yielded inconsistent results. We have performed a systematic review and meta-analysis to summarize the effects of CGs on cancer risk and mortality. METHODS: PubMed, Scopus, Cochrane library, Medline and Web of Knowledge were searched for identifying relevant studies. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects model. RESULTS: We included 14 case-control studies and 15 cohort studies published between 1976 and 2016 including 13 cancer types. Twenty-four studies reported the association between CGs and cancer risk and six reported the association between CGs and mortality of cancer patients. Using CGs was associated with a higher risk of breast cancer (RR = 1.330, 95% CI: 1.247-1.419). Subgroup analysis showed that using CGs increased the risk of ER+ve breast cancer but not ER-ve. Using CGs wasn't associated with prostate cancer risk (RR = 1.015, 95% CI: 0.868-1.87). However, CGs decreased the risk in long term users and showed a protective role in decreasing the risk of advanced stages. CGs use was associated with increased all-cause mortality (HR = 1.35, 95% CI: 1.248-1.46) but not cancer-specific mortality (HR = 1.075, 95% CI: 0.968-1.194). CONCLUSION: The anti-tumor activity of CGs observed in pre-clinical studies requires high concentrations which can't be normally tolerated in humans. However, the estrogen-like activity of CGs could be responsible for increasing the risk of certain types of tumors.

The Associations of Atrial Fibrillation With the Risks of Incident Invasive Breast and Colorectal Cancer.

Atrial fibrillation (AF) is a common arrhythmia that poses a significant risk of stroke. Cross-sectional and case-control studies have shown evidence of associations between AF and breast or colorectal cancer, but there have been no longitudinal studies in which this has been assessed. We prospectively examined a cohort of 93,676 postmenopausal women enrolled in the Women's Health Initiative from 1994 to 1998 to determine whether there are relationships between baseline AF and the development of invasive breast or colorectal cancer. The prevalence of self-reported physician diagnosis of AF at baseline was 5.1%. Over approximately 15 years of follow-up, the incidence of invasive breast cancer was 5.7%, and the incidence of colorectal cancer was 1.6%. Adjusted hazard ratios and 95% confidence intervals were obtained using Cox proportional hazards models. We found no significant association between AF and incident colorectal cancer, but we did see a 19% excess risk of invasive breast cancer among those with AF (adjusted hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.03, 1.38). Additional adjustment for baseline use of cardiac glycosides attenuated the association between AF and invasive breast cancer (HR = 1.01, 95% CI: 0.85, 1.20). Cardiac glycoside use was strongly associated with incident invasive breast cancer (HR = 1.68, 95% CI: 1.33, 2.12) independent of AF and other confounders. Mechanisms of the associations among breast cancer, AF, and cardiac glycosides need further investigation.

Cardiac glycosides and breast cancer risk: A systematic review and meta-analysis of observational studies.

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I2 = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.

Plant-derived cardiac glycosides: Role in heart ailments and cancer management.

Cardiac glycosides, the cardiotonic steroids such as digitalis have been in use as heart ailment remedy since ages. They manipulate the renin-angiotensin axis to improve cardiac output. However; their safety and efficacy have come under scrutiny in recent times, as poisoning and accidental mortalities have been observed. In order to better understand and exploit them as cardiac ionotropes, studies are being pursued using different cardiac glycosides such as digitoxin, digoxin, ouabain, oleandrin etc. Several cardiac glycosides as peruvoside have shown promise in cancer control, especially ovary cancer and leukemia. Functional variability of these glycosides has revealed that not all cardiac glycosides are alike. Apart from their specific affinity to sodium-potassium ATPase, their therapeutic dosage and behavior in poly-morbidity conditions needs to be considered. This review presents a concise account of the key findings in recent years with adequate elaboration of the mechanisms. This compilation is expected to contribute towards management of cardiac, cancer, even viral ailments.

Cardiac glycosides use and the risk of lung cancer: a nested case-control study.

BACKGROUND: Two studies have reported statistically significant associations between the use of cardiac glycosides (CGs) and an increased risk of lung cancer. However, these studies had a number of methodological limitations. Thus, the objective of this study was to assess this association in a large population-based cohort of patients. METHODS: We used the United Kingdom Clinical Practice Research Datalink (CPRD) to identify a cohort of patients, at least 40 years of age, newly-diagnosed with heart failure, or supra-ventricular arrhythmia. A nested case-control analysis was conducted where each incident case of lung cancer identified during follow-up was randomly matched with up to 10 controls. Exposure to CGs was assessed in terms of ever use, cumulative duration of use and cumulative dose. Rate ratios (RRs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression after adjusting for potential confounders. RESULTS: A total of 129,002 patients were included, and followed for a mean (SD) of 4.7 (3.8) years. During follow-up, 1237 patients were newly-diagnosed with lung cancer. Overall, ever use of CGs was not associated with an increased risk of lung cancer when compared to never use (RR = 1.09, 95% CI: 0.94-1.26). In addition, no dose-response relationship was observed in terms of cumulative duration of use and cumulative dose with all RRs around the null value across quartile categories. CONCLUSION: The results of this large population-based study indicate that the use of CGs is not associated with an increased risk of lung cancer.

Treatment characteristics in elderly.

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.

Difficulties in maintaining potassium homeostasis in patients with heart failure.

Potassium (K) concentration plays a significant role in cell metabolism and membrane excitability. The imbalance of serum potassium is important because it can lead to life-threatening events. Potassium balance may be lost both through the neurohormonal mechanisms involved in cardiovascular diseases and through the drugs used in the treatment of this illness. Avoiding both hypo- and hyperkalemia is beneficial in several cardiovascular diseases, especially heart failure. Electrolyte abnormalities are frequently seen complications in subjects with heart failure. Malignant ventricular arrhythmias and sudden cardiac death are particularly feared complications in K+ instability.

Oleander toxicity: an examination of human and animal toxic exposures.

The oleander is an attractive and hardy shrub that thrives in tropical and subtropical regions. The common pink oleander, Nerium oleander, and the yellow oleander, Thevetia peruviana, are the principle oleander representatives of the family Apocynaceae. Oleanders contain within their tissues cardenolides that are capable of exerting positive inotropic effects on the hearts of animals and humans. The cardiotonic properties of oleanders have been exploited therapeutically and as an instrument of suicide since antiquity. The basis for the physiological action of the oleander cardenolides is similar to that of the classic digitalis glycosides, i.e. inhibition of plasmalemma Na+,K+ ATPase. Differences in toxicity and extracardiac effects exist between the oleander and digitalis cardenolides, however. Toxic exposures of humans and wildlife to oleander cardenolides occur with regularity throughout geographic regions where these plants grow. The human mortality associated with oleander ingestion is generally very low, even in cases of intentional consumption (suicide attempts). Experimental animal models have been successfully utilized to evaluate various treatment protocols designed to manage toxic oleander exposures. The data reviewed here indicate that small children and domestic livestock are at increased risk of oleander poisoning. Both experimental and established therapeutic measures involved in detoxification are discussed.

Diagnóstico de la intoxicación digitálica

El tratamiento con glucósidos cardiotónicos es benéficio para muchos pacientes con problemas cardiacos, pero los efectos electrofisiológicos adversos relacionados con niveles tóxicos de estos fármacos derivados de la digital representan un grave riesgo.

Therapeutic range of cardiac glycosides.

The narrow therapeutic range of cardiac glycosides continually challenges chemists to synthetize new derivatives with improved therapeutic properties. One of the best investigated semi-synthetic glycosides is 16 alpha-gitoxin. Compared to ouabain and gitoxin, it produces positive inotropic effects on the isolated guinea-pig heart in a wider range of concentrations and causes less pronounced rhythmic disturbances. These results were confirmed by electrophysiological investigations in isolated fibres of the canine myocardium and of the Purkinje system, by investigations in the anaesthetized cat and dog and in healthy volunteers. The effects of various semi-synthetic compounds (e.g. actodigin, ASI-222) are described and possibilities to trigger these effects are discussed. Of some significance seem to be differences in the structure of the (Na+ + K+)-ATPase system of different tissues, e.g. the working muscle and the Purkinje system of the heart, as well as differences due to the formation and dissociation of the glycoside-enzyme complex. The significance of K+, Ca2+ and of several pharmacokinetic parameters (e.g. the volume of distribution) for these reactions are briefly discussed.

A literature survey of the potentially adverse effects of the drugs commonly prescribed for the elderly.

Part I: Hard data concerning adverse drug reactions are notoriously difficult to obtain. Some of the problems arise because of: --patient variables including age, sex, genetic differences, and current illness. --multiple drug use, continuation of smoking, and use of alcohol. --variations in dose, duration of treatment, and route of administration. --some effects are not reported but many reported effects are not truly due to the drug indicated. Nevertheless, we need to be aware of potential adverse reactions. Our ability to recognize drug side effects will be improved if we have some idea which kinds of reaction may occur. Part I deals with the analgesics, sedatives, laxatives, antacids, antidiabetic agents, antihypertensives and cardiovascular drugs. Potential systemic and ocular adverse reactions are listed.