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Serum digoxin levels in elderly nursing home patients: appraisal of routine periodic measurements.

An assessment was made of the clinical value of routine periodic measurement of serum digoxin levels in 51 elderly nursing home patients with cardiac disease. The findings showed that the serum digoxin level was not correlated with the dosage of digoxin nor the patient's clinical state of digitalization. All patients were effectively digitalized, as judged clinically, and no digitalis toxicity occurred despite a wide range of serum digoxin levels. When adequate medical supervision, electrocardiograms, roentgenograms, serum electrolyte determinations and renal function tests are available, the routine periodic measurement of serum digoxin concentration does not offer any additional benefit in the management of nursing home patients with cardiac disease.

Aged↗

Serum digoxin concentration and age.

A review was conducted of the charts of 79 consecutive inpatients (age range, 17-93 years) who were in a steady state with respect to digoxin dosage, and had serum creatinine levels below 1.6 mg/dl or urea nitrogen levels below 26 mg/dl. In these patients whose renal function was not impaired, there was no correlation between age and the serum digoxin level normalized for dosage. Concurrent administration of quinidine significantly elevated digoxin concentration. Patients with congestive heart failure showed a higher serum digoxin level than did those without heart failure. Thus, age appeared to have little, if any effect on the relationship between the dose of digoxin and the steady-state serum level when the factor of impaired renal function (often associated with aging) was eliminated.

Adolescent↗

Monitoring digoxin therapy in two long-term facilities.

Digoxin monitoring was examined according to 13 criteria in two nursing homes: 1) an intermediate care facility (ICF) with private physicians, and 2) a skilled care (SCF) plus ICF with 3 housestaff physicians from a identify all patients receiving digoxin, 2) evaluate dosage patterns, 3) evaluate monitoring patterns, and 4) detect possible toxic reactions and determine whether management was appropriate. The calculated correct dosage of digoxin in both ICFs. More frequent monitoring of serum creatinine and potassium levels was associated with fewer symptoms of toxicity. Possible toxicity occurred in 46 percent of the SCF and in 68 and 71 percent of patients in the ICFs. Documented toxicity occurred in 18 percent of the SCF patients and in 16 and 10 percent of the ICF patients. Eighty percent of patients who had symptoms of digoxin toxicity were not examined or managed appropriately in the SCF, and 43 and 33 percent in the ICFs. Often standing orders had been assigned for drugs to treat nausea, vomiting or diarrhea. A number of possible drug interactions with digoxin were discovered. The participation of the pharmacist in nursing home care is discussed.

Aged↗

Mammary excretion of digoxin in goats.

The binding of digoxin to proteins in plasma and milk was about 20% lower after the addition of the drug to plasma and milk (in vitro) than its binding in plasma and milk from animals administered digoxin parenterally. The mammary excretion of digoxin was examined in the experiments on goats. The concentration of non-protein-bound digoxin in milk was slightly lower than the concentration of non-protein-bound in plasma suggesting a passive diffusion. The amount of digoxin excreted with the milk per day should be far below the dose usually recommended for a newborn child.

Animals↗

Effects of platelet-activating factor antagonists WEB 2086 and BN 50730 on digoxin-induced arrhythmias.

Effects of platelet-activating receptor antagonists WEB 2086 (1.0-30.0 mg.kg-1 intravenously) and BN 50730 (10.0 mg.kg-1 intravenously) alone or in combination with CGS 8515 (a specific 5-lipoxygenase inhibitor, 0.3 mg.kg-1 intravenously) and Dazmegrel (a thromboxane synthase inhibitor, 1.0 mg.kg-1.hr-1 intravenous infusion) on digoxin-induced arrhythmias were investigated in anaesthetised guinea-pigs. ECG, mean arterial blood pressure, heart rate and arrhythmias were recorded, starting 30 min. before digoxin administration and continuing for 60 min. afterwards. WEB 2086 (10.0 mg.kg-1 intravenously) reduced the mortality rate and arrhythmia score significantly compared to the control values. However, in combination with CGS 8515, it did not affect the mortality rate. BN 50730 (10.0 mg.kg-1) reduced the incidence of ventricular fibrillation and also arrhythmia score. BN 50730 in combination with Dazmegrel was reduced the arrhythmia score, incidence of ventricular fibrillation and mortality rate significantly, compared to control values. Digoxin-induced acute rise in mean arterial blood pressure was not affected by any of drug treatment except WEB 2086 (10.0 mg.kg-1) in combination with CGS 8515. Heart rate values did not differ between groups. However, pressure-rate index was reduced by WEB 2086 alone or in combination with CGS 8615. Results showed that although two different platelet-activating factor antagonists have different effects on the incidence of ventricular fibrillation and mortality, they improved the digoxin-induced arrhythmias when they were used either separately or in combination with CGS 8515 or Dazmegrel by implicating that platelet-activating factor has a role on digoxin-induced arrhythmias.

Animals↗

Acquired colour vision deficiency in patients receiving digoxin maintenance therapy.

BACKGROUND/AIMS: Disturbances of colour vision are a frequently reported sign of digoxin toxicity. The aim of this study was to investigate the incidence of acquired colour vision deficiency in elderly hospitalised patients receiving maintenance digoxin therapy. METHODS: 30 patients (mean age 81.3 (SD 6.1) years) receiving digoxin were tested using a battery of colour vision tests (Ishihara, AO Hardy Rand Rittler plates, City tritan test, Lanthony tritan album, and the Farnsworth D15). These were compared to an age matched control group. Serum digoxin concentrations were determined from venous blood samples. RESULTS: Slight to moderate red-green impairment was found in approximately 20-30% of patients taking digitalis, and approximately 20% showed a severe tritan deficiency. There was no correlation between colour vision impairment and serum digoxin level. CONCLUSIONS: Formal colour vision testing of elderly patients taking digitalis showed a high incidence of colour deficiency, suggesting that impairment of retinal function can occur even at therapeutic drug levels. As a result, colour vision testing in this population would have limited value for the detection of drug toxicity.

Aged↗

Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients.

The need for maintenance digoxin treatment was assessed in a double-blind, variable-dose, crossover comparison with placebo. Forty-six outpatients who had been prescribed the drug for heart failure were studied; 33 were in sinus rhythm and the remainder in atrial fibrillation. Mean serum digoxin concentrations in those with sinus rhythm averaged 1-33 nmol/l, but a lower concentration, averaging 0-97 nmol/l, was accepted in those with atrial fibrillation as six of them developed bradycardia. Sixteen of the 46 patients deteriorated on placebo, and eight completely recovered when digoxin was reintroduced; in the remainder additional diuretics were required temporarily. Spirometric values deteriorated on changing to placebo whether or not the patient showed clinical evidence of recurrence of heart failure. In a separate study of nine patients who showed no clinical evidence of deterioration on placebo, reintroduction of digoxin caused a shortening of left ventricular ejection time, which persisted for at least a month. This suggests that the inotropic response to digoxin is sustained during maintenance treatment.

Atrial Fibrillation↗

Maintenance of the inotropic effect of digoxin on long-term treatment.

M-mode echocardiograms and systolic time intervals were recorded before and six weeks after stopping digoxin in 11 patients in sinus rhythm to see whether the inotropic effect of digoxin was maintained with long-term treatment. Significant changes indicating a reduction in inotropic state on stopping digoxin were observed in the group. Clinical deterioration occurred in only one patient, associated with evidence of initially impaired cardiac function rather than an atypical response to digoxin. This study provides evidence that chronic digoxin treatment does continue to exert a positive inotropic effect.

Adult↗

Digoxin-like immunoreactive substance in patients with aneurysmal subarachnoid haemorrhage.

Digoxin was measured by radioimmunoassay in the plasma of 25 patients with aneurysmal subarachnoid haemorrhage who had not received digoxin treatment. After heating the plasma an endogenous substance cross reacting with antibodies to digoxin was identified in 18 cases. The presence of this substance was significantly related to the total amount of blood and to the presence of blood in the frontal interhemispheric fissure and could not be explained by hypertension or intake of water and sodium. A negative sodium balance and volume depletion occurred more often in patients who were positive for digoxin, but this relation did not reach statistical significance. It is concluded that a digoxin-like natriuretic factor is released in response to a subarachnoid haemorrhage, probably as a result of hypothalamic damage.

Aged↗

Measurement of plasma digoxin concentration by radioimmunoassay.

A rapid, sensitive, and precise method for measuring the plasma digoxin concentration has been developed with the radioimmunoassay technique. Seventy patients receiving digoxin were shown to have plasma digoxin concentrations between 0.4 and 5 ng./ml. Preliminary studies show that though there is a positive correlation between total daily dose and the plasma digoxin concentration, the relationship is not close, and a relatively wide range of plasma digoxin concentrations appear to be consistent with effective digitalization.

Animals↗

Geographic differences in digoxin inactivation, a metabolic activity of the human anaerobic gut flora.

The inactivation of digoxin by conversion to reduced metabolites (digoxin reduction products, or DRP), a function of the anaerobic gut flora, was studied in normal volunteers from southern India and the United States. Digoxin was metabolised to DRP by 28 (13.7%) of 204 healthy south Indians in contrast to 67 (36.0%) of 186 New Yorkers (p less than 1 X 10(-6)). Only 1.0% of Indians compared with 14.0% of Americans excreted large amounts of metabolites (greater than 40% DRP) in the urine (p less than 1 X 10(-5)). Of 104 urban Indians, 23 (22.1%) were metabolisers, in contrast with five of 100 rural villagers (p less than 0.001). Within the urban group, digoxin metabolism correlated with education, frequency of animal protein intake, and most significantly, personal income. Organisms capable of reducing digoxin in vitro were found with similar frequencies in stool cultures from Indians and Americans. In the cultures of some subjects, DRP production was inhibited at lower dilutions but expressed at higher dilutions. We conclude that variations in drug metabolism between population groups may result from differences in the metabolic activity of the anaerobic gut flora probably mediated by environmentally determined factors.

Adolescent↗

Placebo controlled trial of xamoterol versus digoxin in chronic atrial fibrillation.

Thirteen patients in chronic atrial fibrillation with a normal resting heart rate but with exercise tachycardia and episodes of bradycardia were randomised to treatment periods of two weeks on xamoterol (200 mg twice daily), low dose digoxin, or placebo, in a blind crossover study. The results (mean SEM) of symptom scores, a treadmill exercise test, and 24 hour ambulatory electrocardiographic monitoring were obtained. Xamoterol improved symptom scores and controlled exercise heart rate better than digoxin. Xamoterol was better than digoxin or placebo in reducing the heart rate response to exercise and tended to improve exercise duration. Xamoterol, by reducing the daytime maximum hourly heart rate and increasing the night time minimum hourly heart rate, significantly reduced the difference between the two compared with placebo. In contrast, digoxin tended to reduce both the maximum and minimum hourly heart rates through day and night. Both the frequency and duration of ventricular pauses were reduced by xamoterol but tended to increase with digoxin. Xamoterol reduced both the circadian variation in ventricular response to atrial fibrillation and exercise tachycardia by modulating the heart rate according to the prevailing level of sympathetic activity. These changes were translated into symptomatic benefit for the patients studied.

Adrenergic beta-Agonists↗

Inhibition of Na(+)-K(+)-ATPase by digoxin and its relation with energy expenditure and nutrient oxidation rate.

This study investigates the effects of digoxin, an inhibitor of the Na+ pump (Na(+)-K(+)-ATPase), on resting metabolic rate (RMR), respiratory quotient (RQ), and nutrient oxidation rate. Twelve healthy male subjects followed a double-blind protocol design and received either 1 mg/day digoxin or a placebo 2 days before indirect calorimetry measurements. Digoxin induced a 0.22 +/- 0.07 kJ/min or 3.8 +/- 1.5% (mean +/- SE, P = 0.01) decrease in RMR and a 0.40 +/- 0.13 kJ/min (P = 0.01) decrease in fat oxidation rate, whereas carbohydrate and protein oxidation rates did not change significantly. A dose-response relationship between serum digoxin and RQ was observed. These results suggest that digoxin reduces not only RMR but also fat oxidation rate by mechanisms that remain to be elucidated. Because a linkage and an association between genes coding the Na(+)-K(+)-ATPase and the RQ have been previously observed, the present demonstration of an effect of Na(+)-K(+)-ATPase inhibition on fat oxidation rate strengthens the concept that the activity of this enzyme may play a role in body weight regulation.

Adult↗

Centrally mediated effect of phenytoin on digoxin-induced ventricular arrhythmias.

Studies on the efficacy of phenytoin administered directly into the cerebrospinal fluid in protecting against digoxin-induced arrhythmias were carried out in 20 anesthetized dogs. Phenytoin was administered in an average dose of 10 mg directly into the cisterna magna of 10 dogs. The other control dogs received only the vehicle for phenytoin intrathecally. Both groups of dogs subsequently received a toxic dose of digoxin (0.2 mg/kg) intravenously. The time after intravenous digoxin to the onset of ventricular premature beats, ventricular tachycardia and ventricular fibrillation (VF) was significantly shorter in control animals compared to the phenytoin-treated dogs. In the control group, one dog survived the 3-h observation period without developing ventricular fibrillation, whereas 5 of the 10 phenytoin-treated dogs survived this period without VF (P less than 0.05). Phenytoin had a similar protective effect against digoxin-induced arrhythmias in 10 other dogs that received phenytoin intravenously. In the animals that received phenytoin intrathecally, plasma concentrations of phenytoin were undetectable. Thus, in this experimental model, phenytoin exerts a protective effect against digoxin-induced ventricular arrhythmias which is mediated via the central nervous system.

Animals↗

Possible contribution of leukotrienes in the arrhythmogenic effects of digoxin on isolated guinea-pig hearts.

The effect of a leukotriene D4 (LTD4) receptor antagonist, L-648,051, was investigated in digoxin-induced cardiac toxicity in isolated guinea-pig hearts (Langendorff preparation). Digoxin infusion (25 microg.ml-1, 0.5 ml.min-1) increased perfusion pressure and contractile force initially, but decreased them later. The onset of first ventricular premature beats (VPBs) matched the increase phase, but the decrease phase was accompanied by ventricular tachycardia (VT) and fibrillation (VF). In the presence of L-648,051 (5 micromol. l-1), the initial phase was similar to that observed with digoxin alone, but the marked reduction was inhibited. This drug increased the concentration of digoxin required for VBSs and cardiac arrest, but it could not prevent the formation of VT and VF. The duration of VT was significantly decreased by L-648,051. It is concluded that the leukotriene receptor antagonist might have beneficial effects on digoxin-induced arrhythmias. Whether this effect depends on direct or indirect actions is uncertain.

Animals↗

Hypothalamic digoxin, hemispheric dominance and the acquired immunodeficiency syndrome.

OBJECTIVES: Hypothalamic digoxin, an isoprenoidal metabolite, is an endogenous regulator of membrane Na(+)-K(+) ATPase activity, immune activation and synaptic neurotransmission. The objective of this study was to assess the role of hypothalamic digoxin and hemispheric dominance in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and in the genesis of sexual orientation. METHODS: The isoprenoid-pathway-related cascade - (i) isoprenoidal metabolites - digoxin, dolichol and ubiquinone, (ii) tryptophan/tyrosine catabolic patterns, (iii) glycoconjugate metabolism, (iv) free radical metabolism and (v) membrane composition were assessed in AIDS (CDC stage - group IV - subgroup C), individuals with differing hemispheric dominance as well as in individuals with differing sexual orientation. Statistical analysis was done by Student's t test with modified degrees of freedom. RESULTS: The HMG CoA reductase activity was increased with increased digoxin and dolichol levels and reduced ubiquinone levels in AIDS. The membrane Na(+)-K(+) ATPase activity and serum magnesium levels were reduced. The tryptophan catabolites (serotonin, quinolinic acid, nicotine and strychnine) were increased and the tyrosine catabolites (morphine, dopamine and noradrenaline) were reduced. The serum glycoconjugate metabolites were increased and lysosomal stability was reduced in AIDS. There was reduced incorporation of glycoconjugates into membranes and an increased membrane cholesterol:phospholipid ratio. Lipid peroxidation products and NO were increased while free radical scavenging enzymes and reduced glutathione were reduced. The biochemical patterns obtained in AIDS correlated with those obtained in right-hemispheric dominance and homosexuals/bisexual states. CONCLUSIONS: Hypothalamic digoxin and right-hemispheric dominance is important in the predisposition to AIDS as well as homosexual/bisexual states.

Acquired Immunodeficiency Syndrome↗

Assessment of methodology in single-dose studies of digoxin bioavailability.

Eight healthy males received 0.75 mg of digoxin by ten modes of administration in a single-dose multicrossover bioavilability study. Digoxin concentration in multiple blood samples drawn after each dose and in six consecutive 24-hour urine collections were used to calculate the areas under the 4-, 8-, and 24-hour serum concentration curve (A-4, A-8, A-24), and the excretion of digoxin during 1 day (U-1) and 6 days (U-6) following each dose. All five methods of assessment gave very similar information on bioavailability. Individual values of A-4 and A-8 were highly correlated (r=0.973) and had similar variability. A-24 was more variable than A-4 and A-8, and was not as well correlated with either. U1- and U-6 were highly correlated (r=0.944), and had nearly identical variability which was less than that of any of the area measures. Thus, urinary excreation data provides more reliable and reproducible information about completeness of absorption of digoxin than data based upon serum concentrations. Extending the period of urine collection beyond 1 day or the blood sampling period beyond 4 or 8 h does not enhance the reliability or usefulness of digoxin bioavailability studies.

Administration, Oral↗

Age-associated changes in tissue distribution and uptake of 3H-digoxin in mice and guinea pigs.

The influence of age on tissue distribution of digoxin in mice and guinea pigs and uptake by mouse heart slices was investigated. 4 h after a single dose of 3 H-digoxin, tissue:plasma ratios were significantly greater in very young animals and declined with increasing age. A similar relationship was apparent for packed red blood cell:plasma concentration ratios in mice. Uptake of 3H-digoxin by heart tissue slices was also higher for 21-day-old mice than 200-day-old mice. These data seem to correlate with the larger volume of distribution of digoxin observed in the young. Tissue digoxin relative to plasma concentration seems higher in the young, although they appear less sensitive to the effects of cardiac glycosides.

Aging↗