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Biomedical subjects

L Storstein

Publications and source records attributed to L Storstein.

87 records · Page 5Linked to original sources
PubMed1976

Studies on digitalis. V. The influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin.

The aim of the present investigation is to study digitoxin and digoxin protein binding in patients with normal renal and hepatic function, in patients with uremia, and in patients under treatment with hemodialysis for renal failure. The binding of digitoxin and cardioactive metabolites to serum proteins was studied using equilibrium dialysis (an in vitro chemical assay) alone and in combination with a modified 86Rb method. The following values for protein binding were found: DT-3 (digitoxin), 95.7%; DT-2 (digitoxigenin-bis-digitoxoside), 96.5%; DT-1 (digitoxigenin-mono-digitoxoside), 98.7%; DT-0 (digitoxigenin), 92.7%; DG-3 (digoxin), 21.2%; DG-2 (digoxigenin-bis-digitoxoside), 16.3%; DG-1 (digoxigenin-mono-digitoxoside), 18.5%; and DG-0 (digoxigenin), 13.3%. In vitro addition of procainamide, phenytoin, heparin, and rifampicillin did not influence the in vitro binding of digitoxin. Protein binding of digitoxin showed small individual variations in patients with normal renal and hepatic function. Uremia per se did not influence the in vitro binding of digitoxin. There were marked changes in digitoxin and digoxin protein binding during an 8-hr hemodialysis, digitoxin binding decreasing from 97.1% to 93.7% (p less than 0.0025) and digoxin binding from 23.5% to 15.4% (p less than 0.05). In the uremic patient the metabolic pattern of digitoxin tended toward a decrease in protein-bound metabolites.

Blood Proteins↗
PubMed1976

Studies on digitalis. VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites.

Serum protein binding of digitoxin was lower (p less than 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimation was 4.8 days and 8.1 days in 5 control subjects (p less than 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p less than 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.

Blood Proteins↗
PubMed1975

[Digitalis].

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Digitalis Glycosides↗
PubMed1975

Studies on digitalis. III. Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites.

Simultaneous serum, urine, and bile measurements of digitoxin and its cardioactive metabolites were preformed in 5 cholecystectomized patients with T tube drainage. A 86Rb method was used for serum and urine analysis. The recovery of digitoxin and cardioactive metabolites in two extractions with dichloromethane was 93%; 7% was left in bile. Peak bile concentrations had a mean value of 41.6 ng/ml and were seen after 15 to 60 min. Bile concentration was higher than serum and urine concentration after 24 hr. Mean T/2 of serum elimination was 4.3 days and 8.1 days in 5 control subjects (p less than 0.01). Mean urine concentration T/2 was 10.4 days and 7.2 days in the control subjects (not significant). Mean bile concentration T/2 was 3.5 days. Urinary excretion of digitoxin and cardioactive metabolites was the same in the two groups. The biliary fistula group excreted 22.5% in urine and bile of a dose after 8 days, whereas it was 15.8% in the control subjects. The ratio between the cumulative excretion in urine and bile varied between 1.6 and 2.2. These findings demonstrate that direct interruption of the enterohepatic circulation leads to a marked reduction in serum half-time of digitoxin and cardioactive metabolites, but T/2 is still longer than for other glycosides, indicating that factors other than the enterohepatic circulation are of importance in the slow elimination of digitoxin.

Adult↗
PubMedDate not supplied

Effect of cardiopulmonary bypass with heparin administration on digitoxin pharmacokinetics, serum electrolytes, free fatty acids, and renal function.

In 14 patients investigated before, during, and after extracorporeal circulation, serum digitoxin concentration fell significantly during bypass but returned to preoperative values within 24 hr. Both changes occurred in parallel with changes in hematocrit. Serum magnesium concentration fell markedly just before and during bypass and returned to preoperative values on the third and fourth postoperative days. Urine digitoxin concentration fell on the day of operation and remained low in the postoperative period, with a concomitant reduction in the renal excretion of digitoxin. Creatinine and digitoxin clearances decreased on the day of operation and returned slowly to control values during the postoperative period. In 5 other patients, serum digitoxin protein binding decreased significantly during bypass due to heparinization and was normalized by administration of protamine sulfate. Free fatty acids increased significantly immediately before bypass and returned to normal toward its end. The marked changes in digitoxin serum levels during cardiopulmonary bypass can be explained by hemodilution. Acute deterioration of renal function does not lead to accumulation of digitoxin. Heparin administration causes major changes in free fatty acids and serum digitoxin protein binding without important changes in the free digitoxin concentration. Digitoxin can thus be safely administered to patients undergoing cardiac surgery with extracorporeal circulation.

Aged↗
PubMedDate not supplied

Correlation between pharmacokinetics and intropic and electrophysiologic responses to digitoxin in the intact dog.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

Animals↗
PubMedDate not supplied

Effects of autonomic blockade on the inotropic and electrophysiologic response to digitoxin in the intact dog.

Inotropic and electrophysiologic effects in dogs of a single dose of digitoxin with and without autonomic blockade with propranolol plus atropine were observed for 8 hr. Left heart catheterization and His bundle registration were performed in 14 Labrador dogs anesthetized with pentobarbital. Pacing and programmed electrical stimulation were used to determine heart rate-independent changes in dP/dt, intra-atrial, AV nodal, His-Purkinje, and intraventricular conduction velocity. The effective and the functional refractory periods of the atrium, and the functional nodal refractory period (AV-FRP) were measured. Six dogs were given propranolol 0.5 mg/kg plus atropine 0.05 mg/kg every hour. After determination of inotropic and electrophysiologic parameters, digitoxin (2.0 mg) was given to 5 of the dogs, while 1 dog served as control. The other 8 dogs were given only digitoxin (2.0 mg). The dP/dt increased after digitoxin in both groups with maximum values after 2 hr. The autonomic nervous system had only minor influence on changes in contractility caused by digitoxin. The marked fall in heart rate and increase in A-H time (i.e., AV nodal conduction time) and AV-FRP after digitoxin were almost completely blocked by atropine and propranolol. Minor increases in A-H time and AV-FRP indicated a slight direct effect of digitoxin on the AV node.

Animals↗
PubMedDate not supplied

Effect of intravenous and oral pindolol on exercise tolerance and electrocardiographic changes in angina pectoris.

The effects of intravenous (0.4 mg) and oral pindolol (5 mg, t.i.d.) on exercise tolerance and electrocardiographic ST-segment changes were investigated in 20 patients with documented coronary artery disease (16 males and 4 females; mean age, 56.7 years). A randomized double-blind crossover design was used, and graded submaximal exercise was performed on a bicycle ergometer. Pindolol significantly decreased heart rate at rest, and during and after exercise. The time intervals before the appearance of ST depression, before anginal pain, and before the cessation of work were significantly increased after beta-adrenergic blockade, and work tolerance was enhanced, both indicating that pindolol is an effective antianginal agent. Angina appeared at a lower heart rate after pindolol. Anginal pain and cessation of work were associated with significantly less ST-segment depression after pindolol, suggesting that the relation between ST depression and myocardial ischemia is altered by beta-adrenergic blockade. The appearance and disappearance of ST-segment changes correlated closely with heart rate during placebo and pindolol treatment. Heart rate thus seems to be a major determinant of ST-segment depression during and after exercise in coronary artery disease.

Administration, Oral↗
PubMedDate not supplied

Protein binding of cardiac glycosides in disease states.

Digitoxin in 97% bound to serum albumin and digoxin only to the extent of 24%. Hypoalbuminaemia significantly changes the protein binding of digoxin in Kwashorkor serum and the binding of digitoxin in patients with chronic active hepatitis and the nephrotic syndrome. Sprue patiens with normal albumin values have normal binding of digitoxin. Preliminary data in patients with thyrotoxicosis and myxoedema show digitoxin binding within the normal range. The effect of uraemia per se on digitoxin binding is controversial as both normal and slightly decreased values have been reported. In uraemic patients on treatment with haemodialysis, heparin administration has been shown to be a powerful serum binding displacing agent for both digitoxin and digoxin, the mechanism probably being a heparin-induced release of free fatty acids. Patients with a significant decrease in serum protein binding of digitoxin or digoxin should be maintained on a total serum concentration lower than usually considered within the therapeutic range.

Blood Proteins↗