Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the effect of prolonged digitoxin administration on contractile function of nonfailing myocardium, right ventricular papillary muscle mechanics were examined after 6 or 24 wk of glycoside administration to control and pulmonary artery banded cats. Resting length-tension relations were not affected by digitoxin; however, isometrically developed force and the maximal rate of force development at the peak of the length-tension curve were increased in all treated groups. In untreated animals, banding resulted in a 28% incidence of deaths from heart failure. 6 wk after constriction, contractile function was depressed whereas normal function was observed 24 wk after banding. Digitoxin significantly reduced mortality from heart failure and enhanced the recovery of contractile function; contractile function in the 6 wk banded treated group approached that of untreated control and 24-wk banded groups. The long-term effects of digitoxin on contractile function were not importantly related to the temporal association between banding and institution of glycoside administration. Development of myocardial hypertrophy was comparable in treated and untreated banded groups.These results demonstrate that a significant positive inotropic effect persists in both normal and nonfailing hypertrophied myocardium during chronic digitoxin administration.
 ...
PMID:The effect of chronic digitoxin administration on the contractile state of normal and nonfailing hypertrophied myocardium. 12 47

Digitoxin concentration, measured by radio-immunoassay, was significantly lower in 51 patients in chronic renal failure (23.2 +/- 7.8 mug/l) than in 29 patients in heart failure (26.5 +/- 7.3 mug/l), although both groups were on the same maintenance dose of 0.1 mg daily. Despite a normal serum albumin concentration, digitoxin protein binding was less in uraemic patients than in those with normal renal function. Renal failure did not affect intestinal digitoxin absorption. In patients in chronic renal failure elimination half-time was significantly shorter (5.7 +/- 0.9 days) than in healthy controls (7.6 +/- 1.6 days). There was no significant difference in the excretion of water-soluble ("cardioinactive") digitoxin metabolites in urine between patients in chronic renal and those in heart failure. In patients with normal renal function, of dichloromethane-soluble (cardioactive) metabolites only digitoxin could be demonstrated by thin-layer chromatography. The results indicate that patients in chronic renal failure can safely be given the same dose as those with normal renal function, without danger of over- or underdosage.
 ...
PMID:[Pharmacokinetics of digitoxin in chronic renal failure (author's transl)]. 83 89

R 79595 (N-cyclohexyl-N-methyl-2-[[[phenyl (1,2,3,5-tetrahydro-2 oxoimidazo [2,1-b]-quinazolin-7-yl) methylene] amin] oxy] acetamide) and its isomers represent a novel class of compounds with phosphodiesterase (PDE) inhibitory and cardiotonic (positive inotropic) actions. The cardiac effects of this class of compounds were investigated in the hexobarbital-depressed heart-lung preparation of the guinea-pig. After induction of heart failure (reduction of cardiac output to 25% of the initial value) cumulative addition of R 79595 or its isomers R 80122 (E-isomer) and R 80123 (Z-isomer) concentration-dependently reversed the cardiac depressant effects of hexobarbitone-Na. With regard to reconstitution of contractility and cardiac function R 80122 (E-isomer) was 10 fold more potent than R 79595 (1:1 mixture of the isomers) and nearly 100 fold more potent than R 80123 (Z-isomer). Furthermore, the cardiotonic action of the most potent isomer (R 80122) was compared to the effects of several positive inotropic reference compounds. The order of cardiotonic potency was as follows: (-)-adrenaline > R 80122 = adibendan > digitoxin > milrinone = enoximone > theophylline. Adibendan (EC50 value: 6.7 +/- 1.8 x 10.-8 mol/l), which showed cardiotonic effects in the same concentration range as R 80122 (EC50 value: 6.1 +/- 1.3 x 10(-8) mol/l), was significantly (p < 0.01) less effective than R 80122 with respect to the maximally induceable increase in cardiac output (CO). The cardiotonic effects of R 80122 could be observed in the low concentration range of 3 x 10(-8) to 1 x 10(-6) mol/l, whereas enoximone (EC50 value: 1.2 +/- 0.1 x 10(-5) mol/l) and milrinone (EC50 value: 8.9 +/- 3.5 x 10(-6) mol/l) elicited positive inotropic effects at 100 fold higher concentrations. Digitoxin was 10 fold less and theophylline was 300 fold less potent than R 80122 with regard to reconstitution of heart function. The cardiotonic effects of R 80122 were not accompanied by an increase in heart rate as found with milrinone, theophylline or (-)-adrenaline in this model. Furthermore, the PDE inhibitory effect of R 79595 and its E-isomer R 80122 were investigated in partially purified isoenzymes from guinea-pig ventricles. The IC50 values of R 79595 and R 80122 on PDE I-IV were compared to the IC50 values of adibendan, milrinone, enoximone and theophylline. The selectivity of an inhibitor for PDE III was evaluated by division of its IC50 values on PDE I, II and IV by the IC50 value on PDE III. R 80122 was the most potent and selective PDE III inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Cardiac effects of R 79595 and its isomers (R 80122 and R 80123) in an acute heart failure model. A new class of cardiotonic agents with highly selective phosphodiesterase III inhibitory properties. 147 Feb 28

The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary; bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2
 ...
PMID:Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. 407 5

The narrow therapeutic range of digitalis glycosides and the danger of intoxication has prompted a search for alternative medication in recent years. Substances reducing the pre- and afterload of the heart are suitable therapeutic agents and vasodilators are, therefore, used as adjuvant or alternative therapy. Of all positive inotropic substances only the catecholamines play an established part in the treatment of acute myocardial failure. Pilot studies testing orally administrable positive inotropic substances are being conducted, but for the moment no such drugs are available for routine use. Digitalis still remains the drug of choice for all forms of primary impairment of contractility and/or supraventricular tachyarrhythmias. The appropriate dosage has to be adapted to the estimated lean body mass and, if necessary, reduced in a thin person, Digitoxin is preferentially used in cases with suspected renal insufficiency (especially in elderly patients).
 ...
PMID:[Alternatives to glycoside therapy?]. 664 45

Cardiac insufficiency in the elderly is not a typically age-induced phenomenon, but is rather due to pathological changes of the heart. Renal function, on the other hand, does show age-related deterioration without any apparent pathological changes occurring. For the treatment of cardiac insufficiency in the elderly three groups of drugs are used: diuretics, cardiac glycosides, and vasodilators. When sinusrhythm is still present diuretics should be primarily employed, and in uneffective glycosides, and finally vasodilators. If hypertension is the main cause of heart failure diuretics and vasodilators should be preferred, and glycosides only used in the last instance. Heart failure complicated by tachyarrhythmia should be treated primarily with glycosides, then diuretics and vasodilators. Powerfully as well as long acting diuretics may cause hypovolaemia, hyponatremia, and in particular hypokalaemia in the elderly. Digoxin accumulates with impaired renal function, Digitoxin is not affected by renal function but its half-life is extremely long. In the case of atherosclerotic changes of the vascular system, vasodilators should be employed with caution to prevent extreme drops in blood pressure.
 ...
PMID:[Cardiac insufficiency in the elderly with particular reference to kidney function]. 702 38

Despite many years of using digitalis to treat congestive heart failure, the problem of intoxication has remained unchanged. In nine prospective studies on patients under a maintenance treatment with digoxin the intoxication rate ranged from 15.2% to 27.5%. Other studies have also shown that renal insufficiency was present in 70% of intoxicated patients. In contrast the digitoxin toxicity rate, as shown in two prospective studies from Norway and France on 649 and 2120 patients respectively, resulted in an intoxication rate of 5.8% and 3.2% respectively. The explanation for the discrepancy between the two glycosides seems to be predominantly the influence of renal function on drug elimination. Digoxin is mainly excreted through the kidneys; an impairment of the renal function will therefore lead to a reduced elimination of this drug. In these cases a dose reduction of digoxin is necessary. Digitoxin on the other hand is excreted both through the kidneys and the bile. Impairment of the renal function does, therefore, not lead to any decrease in digitoxin elimination whether in renal disease, during heart failure or in old age. In contrast to digoxin, no dose reduction is necessary with digitoxin when renal function is reduced. Digitoxin is therefore easier to handle in the long term management of cardiac patients with and without renal impairment.
 ...
PMID:[Prospective examinations of digitalis poisoning]. 727 39

A 82-year-old woman was admitted to hospital because of heart failure, vomiting, and pain in the right upper abdomen. During the past three months she had received treatment with 0.07 mg digitoxin twice daily. The ECG showed sinus bradycardia with intermittent complete sinoatrial block. On the basis of the history, clinical presentation and ECG findings digitalis intoxication was suspected. Digitoxin level was 65.23 ng/ml--far beyond the therapeutic range. Laboratory examinations revealed a marked thrombocytopenia (25,000/microliters). The patient was placed on cholestyramine (4g three times daily) to accelerate intestinal excretion of digitoxin. As there were no life-threatening complications there was no indication for treatment with digitalis-specific antibodies. On the 6th day after discontinuation of digitoxin treatment the platelet count showed a marked rise and returned to normal values as from the 12th day.
 ...
PMID:[Digitoxin-induced thrombocytopenia]. 821 11

Digitoxin is frequently used in Norway in the treatment of cardiac failure. Digitalis glycosides may give rise to a number of side effects difficult to separate from disease in the elderly. Six patients aged 77-93 years, treated with digitoxin 0.05 mg/day, were hospitalized due to digitalis intoxication. Mean digitoxin half-life was 25.2 days. This is significantly more than reported in other studies on younger patients. The symptoms of digitoxin intoxication disappeared on discontinuation of medication. The slow elimination of digitoxin may be related to reduced serum albumin concentration. When digitoxin is used in the treatment of heart failure in the very elderly patients, one should be aware of the possibility of digitoxin intoxication, even at a low dose.
 ...
PMID:[Prolonged half-life of digitoxin in the elderly]. 1007 32

Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or beta-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality--being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin.
 ...
PMID:Treatment of congestive heart failure--current status of use of digitoxin. 1152 33


1 2 Next >>