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Pathophysiology : the Official Journal... Dec 2007Cardiotonic steroids (CS) such as ouabain, digoxin and bufalin, are steroidal drugs prepared from the seeds and dried leaves of the genus Digitalis, and the skin and...
Cardiotonic steroids (CS) such as ouabain, digoxin and bufalin, are steroidal drugs prepared from the seeds and dried leaves of the genus Digitalis, and the skin and parotid gland of amphibians, are used as a cardiac stimulant. Steroids similar or identical to the cardiotonic steroids were identified in human tissues. The available literature unequivocally supports the notion that these endogenous CS function as hormones in mammals. Recent studies show that although similar in structure, the different CS exhibit diverse biological responses. This was shown at the molecular, cellular, tissue and whole animal levels. This review summarizes these diversities, raises a possible explanation for their presence and discusses their implication on the physiological role of the different steroids.
PubMed: 17964766
DOI: 10.1016/j.pathophys.2007.09.011 -
Vascular Health and Risk Management 2006About 5 million Americans suffer from heart failure. Given the correlation of heart failure with age and the rising life expectancy, the prevalence of heart failure... (Review)
Review
About 5 million Americans suffer from heart failure. Given the correlation of heart failure with age and the rising life expectancy, the prevalence of heart failure continues to increase in the general population. Sympathetic stimulation intensifies with progressive heart failure. The rationale to use beta-blockers in individuals with impaired myocardial function is based on experimental evidence supporting the notion that prolonged alpha- and beta-adrenergic stimulation leads to worsening heart failure. Until recently, safety concerns have precluded the use of beta-blockers in patients with diabetes and heart failure. However, several large, randomized, placebo-controlled clinical trials such as Metoprolol Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) have shown that beta-blockers can be safely used in patients with diabetes and heart failure. Moreover, beta-blockers significantly improved morbidity and mortality in this population. Based on this evidence, it is now recommended to add beta-blockers such as metoprolol CR/XL with an escalating dosage regimen to the treatment of patients with symptomatic heart failure who already are receiving a stable medical regimen including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, diuretics, vasodilators, or digitalis.
Topics: Adrenergic beta-Antagonists; Carbazoles; Carvedilol; Chronic Disease; Delayed-Action Preparations; Diabetes Complications; Female; Heart Failure; Humans; Male; Metoprolol; Practice Guidelines as Topic; Propanolamines; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome
PubMed: 17319457
DOI: 10.2147/vhrm.2006.2.2.139 -
Clinical Medicine (London, England) 2006The lessons that the physician William Withering learned from his studies of digitalis are still relevant today. This paper highlights four of these lessons and updates...
The lessons that the physician William Withering learned from his studies of digitalis are still relevant today. This paper highlights four of these lessons and updates them using the tools of clinical pharmacology and pharmacoepidemiology. First, Withering learned that failure to prepare digitalis from the foxglove in a standard manner resulted in a product with unpredictable clinical effects. Preparation of medicines from plants since then has not followed similar good practice and medicines have often not been granted marketing authorisation because of variability in their quality. Second, differences in the response to digitalis were noted by Withering, but he had little idea of their basis. Clinical pharmacology has shown that for drugs such as digitalis differences are caused by variability both in receptor sensitivity and in drug disposition. Third, the dose-response characteristics of digitalis were well known to Withering. Modern techniques of measuring response, such as the use of biomarkers, have made such studies easier, although clinical observations remain the gold standard. Fourth, Withering documented many of the adverse effects of digitalis. The use of various modern databases has facilitated the analysis of clinical toxicology and thus of risk-benefit profiles.
Topics: Biological Availability; Digitalis; Digitalis Glycosides; Dose-Response Relationship, Drug; England; History, 18th Century; Pharmacology, Clinical; Phytotherapy; Plant Leaves; Plant Preparations
PubMed: 16956147
DOI: 10.7861/clinmedicine.6-4-393 -
The Journal of Thoracic and... May 2005Atrial tachyarrhythmia is the most common complication after general thoracic surgery and is associated with significant morbidity, longer hospital stay, and higher... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atrial tachyarrhythmia is the most common complication after general thoracic surgery and is associated with significant morbidity, longer hospital stay, and higher costs. We sought to determine whether the use of antiarrhythmic medications is associated with a reduced rate of postoperative atrial tachyarrhythmia.
METHODS
MEDLINE, EMBASE, Cochrane Database of clinical trials (1980-2003), and reference lists of relevant articles were searched for randomized controlled trials with placebo control, general thoracic patients, and noncombined and prophylactic use of the medications. Search, data abstraction, and analyses were performed and confirmed by at least 2 authors. A fixed-effects model was used to perform meta-analyses.
RESULTS
There were 11 unique trials (total n = 1294) that met the inclusion criteria. Calcium-channel blockers and beta-blockers reduced the risk of atrial tachyarrhythmia in 4 and 2 trials, respectively (relative risk of 0.50 and 95% confidence interval of 0.34-0.73; relative risk of 0.40 and 95% confidence interval of 0.17-0.95, respectively). However, beta-blockers tended to increase the risk of pulmonary edema (relative risk, 2.15; 95% confidence interval, 0.74-6.23). Magnesium tested in one unblinded trial also reduced the risk of atrial tachyarrhythmia (relative risk, 0.4; 95% confidence interval, 0.21-0.78). On the other hand, digitalis preparations were found to be harmful because they increased the risk of atrial tachyarrhythmia in 3 trials (relative risk, 1.51; 95% confidence interval, 1.00-2.28). Finally, 2 other medications, flecainide and amiodarone, were each tested in a single small trial, and their effects were associated with great uncertainty.
CONCLUSIONS
Calcium-channel blockers and beta-blockers are effective in reducing postoperative atrial tachyarrhythmia. The use of these medications should be individualized, and possible adverse events of beta-blockers should be taken into account. Randomized clinical trials do not support the use of digitalis in general thoracic surgery. The value of magnesium as a supplement to a main prophylactic regimen should be explored.
Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Calcium Channel Blockers; Digitalis Glycosides; Evidence-Based Medicine; Female; Flecainide; Hospital Costs; Humans; Length of Stay; Magnesium; Male; Middle Aged; Morbidity; Postoperative Complications; Premedication; Preoperative Care; Randomized Controlled Trials as Topic; Tachycardia, Supraventricular; Thoracic Surgical Procedures; Treatment Outcome
PubMed: 15867772
DOI: 10.1016/j.jtcvs.2004.07.042 -
Congestive Heart Failure (Greenwich,... 2004
Topics: Digitalis; Heart Failure; History, 18th Century; Humans; Phytotherapy; Plant Preparations; United Kingdom
PubMed: 15314483
DOI: 10.1111/j.1527-5299.2004.03628.x -
British Journal of Pharmacology Aug 2004The aim of the present study was to investigate the direct effects and action mechanisms of digitalis on the production of corticosterone in rat adrenocortical cells.... (Comparative Study)
Comparative Study
The aim of the present study was to investigate the direct effects and action mechanisms of digitalis on the production of corticosterone in rat adrenocortical cells. Male rats were challenged with digoxin (1 microg ml(-1) kg(-1)) in the presence or absence of adrenocorticotropin (ACTH, 5 microg ml(-1) kg(-1)) administered by intravenous injection to the right jugular vein. Blood samples were collected at 0, 30, 60, and 120 min following the challenge. The concentration of corticosterone in the rat plasma samples was measured by radioimmunoassay. Zona fasciculata-reticularis (ZFR) cells in male rats were prepared and then incubated with or without digoxin or digitoxin in the presence or absence of ACTH (10(-9) m), forskolin (10(-7) m), 8-bromo-cyclic 3' : 5'-adenosine monophosphate (10(-4) m), cyclopiazonic acid (CPA, 10(-5) m), trilostane (10(-6) m), 25-OH-cholesterol (10(-5) m), pregnenolone (10(-5) m), progesterone (10(-5) m), or deoxycorticosterone (10(-5) m) at 37 degrees C for 1 h before collection of the media. Corticosterone or pregnenolone levels were measured by radioimmunoassay. A single injection of digoxin did not alter the basal level of plasma corticosterone, but did inhibit the level of plasma corticosterone released in response to ACTH in vivo. Administration of digoxin or digitoxin decreased both spontaneous and ACTH-stimulated release of corticosterone in vitro. Digoxin (10(-7)-10(-5) m) and digitoxin (10(-7)-10(-5) m), but not ouabain (10(-7)-10(-5) m), dose-dependently inhibited corticosterone production in response to forskolin and 8-Br-cyclic AMP in rat ZFR cells. Both digoxin (10(-6)-10(-5) m) and digitoxin (10(-6)-10(-5) m) attenuated corticosterone production in response to CPA. Digoxin (10(-5) m) or digitoxin (10(-5) m) inhibited cytochrome P450 side-chain cleavage enzyme (cytochrome P450scc) activity (catalyses conversion of cholesterol to pregnenolone in the presence of trilostane) in rat ZFR cells. The enzyme activity of 11 beta-hydroxylase (catalyses conversion of deoxycorticosterone to corticosterone) in ZFR cells was also inhibited by the administration of digoxin (10(-5) m) or digitoxin (10(-5) m).10 These results together suggest that digoxin and digitoxin decrease the release of corticosterone by acting directly on ZFR cells via a Na+, K+-ATPase-independent mechanism involving the inhibition of the activities of adenylyl cyclase, cytochrome P450scc and 11 beta-hydroxylase, as well as the functioning of cyclic AMP and intracellular calcium.
Topics: Adenylyl Cyclases; Animals; Calcium; Cardiotonic Agents; Cells, Cultured; Corticosterone; Digitoxin; Digoxin; Male; Ouabain; Rats; Rats, Sprague-Dawley; Zona Fasciculata; Zona Reticularis
PubMed: 15249423
DOI: 10.1038/sj.bjp.0705777 -
Brazilian Journal of Medical and... Feb 2000This review highlights the current advances in knowledge about the safety, efficacy, quality control, marketing and regulatory aspects of botanical medicines.... (Review)
Review
This review highlights the current advances in knowledge about the safety, efficacy, quality control, marketing and regulatory aspects of botanical medicines. Phytotherapeutic agents are standardized herbal preparations consisting of complex mixtures of one or more plants which contain as active ingredients plant parts or plant material in the crude or processed state. A marked growth in the worldwide phytotherapeutic market has occurred over the last 15 years. For the European and USA markets alone, this will reach about $7 billion and $5 billion per annum, respectively, in 1999, and has thus attracted the interest of most large pharmaceutical companies. Insufficient data exist for most plants to guarantee their quality, efficacy and safety. The idea that herbal drugs are safe and free from side effects is false. Plants contain hundreds of constituents and some of them are very toxic, such as the most cytotoxic anti-cancer plant-derived drugs, digitalis and the pyrrolizidine alkaloids, etc. However, the adverse effects of phytotherapeutic agents are less frequent compared with synthetic drugs, but well-controlled clinical trials have now confirmed that such effects really exist. Several regulatory models for herbal medicines are currently available including prescription drugs, over-the-counter substances, traditional medicines and dietary supplements. Harmonization and improvement in the processes of regulation is needed, and the general tendency is to perpetuate the German Commission E experience, which combines scientific studies and traditional knowledge (monographs). Finally, the trend in the domestication, production and biotechnological studies and genetic improvement of medicinal plants, instead of the use of plants harvested in the wild, will offer great advantages, since it will be possible to obtain uniform and high quality raw materials which are fundamental to the efficacy and safety of herbal drugs.
Topics: Controlled Clinical Trials as Topic; Developed Countries; Developing Countries; Drug Approval; Guidelines as Topic; Legislation, Drug; Phytotherapy; Quality Control
PubMed: 10657057
DOI: 10.1590/s0100-879x2000000200004 -
Clinical Cardiology Oct 1999The study was undertaken to investigate the effect of metoprolol CR/XL on all-cause mortality in patients with heart failure in New York Heart Association (NYHA) class... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The study was undertaken to investigate the effect of metoprolol CR/XL on all-cause mortality in patients with heart failure in New York Heart Association (NYHA) class II-IV. In all, 3,991 patients in NYHA class II-IV who were stable on standard medical treatment, including angiotensin-converting enzyme inhibitors, diuretics, and digitalis, were randomized to metoprolol CR/XL or placebo and uptitrated from 12.5 or 25 mg to 200 mg over an 8-week period and were planned to be followed for a period of 2 years. The study was stopped earlier than planned due to the significant benefit achieved with metoprolol CR/XL on all-cause mortality. Treatment with metoprolol CR/XL was associated with a 34% decrease in all-cause mortality, 38% decrease in cardiovascular mortality, 41% decrease in sudden death, and 49% decrease in death due to progressive heart failure. The average dose of metoprolol CR/XL at the end of the study was 159 mg, and 64% of the patients were receiving 200 mg of metoprolol CR/XL. There was no significant difference in the placebo and active treatment group with regard to permanent discontinuation. Treatment of patients in NYHA class II-IV with metoprolol CR/XL is associated with a significant decrease in total mortality.
Topics: Adrenergic beta-Antagonists; Adult; Aged; Delayed-Action Preparations; Female; Heart Failure; Humans; Male; Metoprolol; Middle Aged; Prognosis; Survival Analysis; Survival Rate; Sweden; Treatment Outcome
PubMed: 10526701
DOI: No ID Found -
Journal of the American College of... May 1997This study sought to examine the hemodynamic and autonomic dose response to digoxin. (Comparative Study)
Comparative Study
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.
Topics: Cardiotonic Agents; Digoxin; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography, Ambulatory; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Ventricular Function, Left
PubMed: 9137214
DOI: 10.1016/s0735-1097(97)00057-0 -
Clinical Cardiology Oct 1994K-strophanthin or digoxin were added to diuretics (all cases) and vasodilators (most cases) for treating advanced congestive heart failure in 22 patients with dilated... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
K-strophanthin or digoxin were added to diuretics (all cases) and vasodilators (most cases) for treating advanced congestive heart failure in 22 patients with dilated cardiomyopathy and sinus rhythm. K-strophanthin (0.125 mg intravenously) or digoxin (0.25 mg orally) were administered daily in two 3-month periods, during which vasodilators and diuretics were kept constant and patients received one of the two digitalis preparations in a double-blind fashion, crossing over to the alternative preparation in the next period. Blindness was assured throughout the trial with a daily intravenous injection of 10 ml normal saline solution either containing K-strophanthin or not, and with daily oral administration of either placebo or active digoxin. At the end of the run-in period, 15 days after starting active preparations, and thereafter every month for the next 6 months, we evaluated left ventricular pump function at rest and patients' functional performance by a cardiopulmonary exercise test. At Day 15, cardiac index and ejection fraction at rest, compared with run-in, were significantly raised with both glycosides; during exercise while on K-strophanthin, peak oxygen consumption was augmented by 1.4 ml/min/kg (p < 0.01) and oxygen consumption at anaerobic threshold by 2.2 ml/min/kg (p < 0.01); corresponding variations on digoxin (-0.1 and +0.3, respectively) were not significant versus run-in. These patterns were duplicated at repeated tests during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Aged; Anaerobic Threshold; Analysis of Variance; Cardiomyopathy, Dilated; Digoxin; Double-Blind Method; Drug Administration Schedule; Exercise Test; Female; Heart Failure; Humans; Male; Middle Aged; Oxygen Consumption; Stroke Volume; Strophanthins; Ventricular Function, Left
PubMed: 8001300
DOI: 10.1002/clc.4960171005