Time course of functional deterioration after coronary artery ligation in rats.

The aim of this study was to investigate the time course of deterioration of functional capacity in the rat after ligation of the left coronary artery. Functional capacity was evaluated from the increase in blood lactate concentrations in 109 rats during a standardised treadmill test. Animals with myocardial infarction were compared with sham operated and normal controls. Functional capacity was followed during a 13 week period and estimations of the functional capacity were performed 1, 3, 7, 9 and 13 weeks after infarction. Coronary artery ligation produced a significant reduction in functional capacity, averaging 47% (p less than 0.01) over the first 3 weeks after myocardial infarction, irrespective of infarct size. In rats with large infarcts, functional capacity remained essentially unchanged throughout the observation period, but rats with small infarcts improved gradually until their measured exercise response was completely normal at the end of the 13 week period.

Negative potassium balance during beta-blocker treatment of hypertension.

Potassium balance was followed in seven hypertensive patients during treatment with timolol. The patients developed a mean 150 mmol total potassium loss. Serum potassium and body weight were not changed. It is suggested that the changes in total body potassium during timolol treatment may be due to mobilization of potassium from the intracellular space, but, since serum potassium did not rise, timolol may also influence renal handling of potassium.

Thiazide-induced potassium loss not prevented by beta blockade.

Potassium balance was followed in 12 subjects with hypertension during treatment either with timolol and hydrochlorothiazide or with timolol, hydrochlorothiazide, and amiloride. Subjects treated with the beta-blocker and thiazide developed potassium depletion, which was prevented by concomitant treatment with amiloride. Thiazide augments timolol-induced potassium loss and it is suggested that the renal handling of potassium is changed by other mechanisms. The decrement in potassium loss during concomitant amiloride treatment cannot be explained.

Suppression of renal excretion of digoxin in hypokalemic patients.

Inulin and digoxin clearances were simultaneously measured in 19 normokalemic and 4 hypokalemic patients. In normokalemia the renal digoxin clearance exceeded the inulin clearance, indicating both glomerular filtration and active tubular secretion of digoxin. The tubular secretion increased with increasing plasma digoxin concentration. In hypokalemia, however, the tubular secretion of digoxin was significantly reduced but increased after the plasma potassium level was raised to normal.

Digoxin concentration in choroid plexus, brain, and myocardium in old age.

Thirteen aged persons receiving digoxin until the time of death were examined by autopsy, and digoxin concentrations were determined in samples from various tissues (the choroid plexus, grey and white brain matter, left and right ventricular and left and atrial myocardium, diaphragm, and musculus psoas major). These concentrations were related to the digoxin dose and duration of treatment. No significant difference was found between the concentration of digoxin in the choroid plexus and left ventricular myocardium, whereas there were significantly lower concentrations in the right ventricular myocardium and still lower concentrations in the other tissues analyzed. Independent of the digoxin dose, the digoxin concentrations in the choroid plexus tended to be lower in persons treated for a short time before death than in those treated for longer periods of time. Similar differences were not observed in the other tissues, suggesting a slower rate of digoxin uptake in the chroid plexus compared with the myocardium and other tissues. The implications of these findings for the effects of digoxin treatment on the production of cerebrospinal fluid are discussed.

Propranolol withdrawal and thyroid hormones in patients with essential hypertension.

The effect of abrupt withdrawal of propranolol on serum concentrations of triiodothyronine (T3) and thyroxine (T4) was investigated in 5 patients with uncomplicated essential hypertension. The patients had been treated from 2 to 18 mo before the study was begun. Doses varied from 160 to 480 mg propranolol daily. Four of the patients studied developed tachycardia, sweating, or tremor within 2 to 6 days after withdrawal of propranolol. In 1 patient reversible ischemic ECG changes were recorded. The serum concentrations of free T3 increased in the 4 patients suffering from withdrawal symptoms. The mean increase on the day the symptoms started was 51% (range, 22 to 74, 2 p = 0.01). This increase in serum-free T3 correlated positively with the serum propranolol concentration on the last day propranolol was given (r = 0.91, 2 p = 0.03). In the one patient, who did not develop withdrawal symptoms, the serum concentration of propranolol was very low, and the free T3 level remained unchanged. No significant changes in serum concentrations of free T4 or total thyroid hormones were found in any of the patients. We suggest that the propranolol withdrawal symptoms are, at least partially, caused by an increase in the thyroid hormone, T3.

Amiloride-induced changes in digoxin dynamics and kinetics: abolition of digoxin-induced inotropism with amiloride.

Digoxin dynamics and kinetics were studied in six healthy subjects with and without amiloride. Amiloride increased mean renal digoxin clearance from 1.3 to 2.4 ml . kg-1 . min-1 (p less than 0.001) due to increased tubular secretion of digoxin, while the glomerular filtration rate was unchanged. This might be caused by an increase in intracellular potassium concentration in the tubular cells provoked by amiloride. In contrast, the extrarenal clearance of digoxin was almost blocked by amiloride; it fell from a mean of 2.1 to 0.2 ml . kg-1 . min-1 (p less than 0.025). Total body clearance tended to fall, but the decrease was not statistically significant. EValuation of myocardial contractility by systolic time intervals revealed a concentration-response relationship between digoxin and changes in preejection period index when digoxin was given alone (rs = 0.750, p less than 0.001). Pretreatment with amiloride abolished this relationship (rs = 0.307, p = NS). Blood pressure and echocardiographically determined left ventricular end-diastolic diameter measurements indicated no changes in the left ventricular post- and preload. It is concluded that amiloride suppressed digoxin-induced inotropism.

Reduction of digoxin-induced inotropism during quinidine administration.

A kinetic and dynamic study of digoxin was performed in 6 healthy subjects, and repeated in the same subjects after administration of quinidine for 1 wk. Myocardial performance evaluated by systolic time intervals increased in parallel with plasma digoxin concentration, whereas left ventricular end-diastolic diameter on echocardiography and arterial blood pressure remained constant. The positive inotropic effect of digoxin was abolished during concomitant treatment with quinidine. Quinidine has been reported to increase the risk of digitoxicity, and therefore the treatment with digoxin and quinidine in combination should be reconsidered.

Interactions between digoxin and potassium-sparing diuretics.

A kinetic and hemodynamic study of digoxin was performed in six healthy subjects and similar studies were performed during digoxin with spironolactone and with triamterene. Spironolactone reduced renal tubular secretion of digoxin and attenuated its positive inotropic effect (evaluated by systolic time intervals and echocardiography) and triamterene reduced the extrarenal elimination of digoxin, but induced no changes in digoxin-elicited inotrophy. It is suggested that the renal handling of digoxin is influenced by the intracellular potassium concentration in the renal tubular cell. The results indicate a drug-receptor interaction between spironolactone metabolites and digoxin at the hypothetical inotropic digitalis receptor. Amiloride has been reported to suppress digoxin inotropism, whereas spironolactone induces minor inhibition and triamterene does not affect digoxin inotropism.

Pharmacokinetics of oral idarubicin in breast cancer patients with reference to antitumor activity and side effects.

The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer. Plasma concentrations were monitored for 72 hours after the first, fourth, and twelfth doses and trough concentrations after 1, 2, 3, 4, 5, 7, 11, and 12 weeks of treatment. The half-lives of idarubicin and idarubicinol were 19 and 60 hours, respectively. No time-dependent changes or cumulation were observed. The metabolic ratio showed little variation. The plasma AUCs of idarubicin and idarubicinol varied between patients but were fairly constant in individual patients. The sum of the plasma AUCs was lower in patients with rapid progression than in patients who responded to treatment. A correlation between this parameter and the relative decrease in the leukocyte counts was demonstrated (p less than 0.05). No correlation was found between the pharmacokinetic parameters and the time to final progression.

Spironolactone-induced changes in digoxin kinetics.

Plasma clearance, volumes of distribution, and renal and extrarenal clearances of digoxin were calculated from plasma digoxin concentrations and urinary excretion of digoxin after intravenous injection of digoxin in 8 subjects. The investigation was repeated in the same subjects during long-term treatment with spironolactone. Increased plasma concentration of digoxin was detected during spironolactone treatment. Calculated plasma and renal clearances of digoxin and the volumes of distribution decreased statistically significant. Near maximal capacity for the tubular secretion of digoxin was found when normal digoxin dosage was used. It is suggested that unless spironolactone decreases the myocardial sensitivity for digoxin, the loading dose as well as the maintenance dose of digoxin should be reduced during treatment with spironolactone.

Digoxin toxicity compared with myocardial digoxin and potassium concentration.

1 Twenty-nine dogs were given digoxin (0.25 mg) by mouth twice daily for eight days. Some of them (group 1) also received diuretics and others (group 2) a mineralocorticoid. The dogs were then given an intravenous bolus injection of digoxin and plasma and cardiac muscle were analysed for digoxin and potassium. 2 In the digitalized dogs, myocardial potassium concentration decreased following the intravenous injection of either 0.05 or 0.15 mg/kg digoxin; in contrast, in those dogs given diuretics or mineralocorticoid the potassium concentration increased. 3 Ventricular arrhythmias occurred after digoxin injection (0.05 mg/kg) in the hypokalemic dogs, in those given a mineralocortocoid and in those dogs which received a toxic digoxin dose (0.15 mg/kg). No arrhythmias where seen in the control (digitalized) group. 4 Myocardial digoxin concentrations were similar in the control digitalized group and in the mineralocorticoid-treated dogs after the intravenous administration of the lower digoxin dose (0.05 mg/kg). The myocardial digoxin concentration was significantly higher in the hypokalemic group and in the group receiving the higher digoxin dose (0.15 mg/kg). 5 There was no obvious relationship between the occurrence of arrhythmias and the myocardial concentration of digoxin or potassium.

Myocardial uptake of digoxin in chronically digitalized dogs.

1 The time course of myocardial uptake of digoxin, increase in contractility and changes in myocardial potassium concentration was studied for 90 min following an intravenous digoxin dose to long-term digitalized dogs. 2 Nineteen dogs were investigated by the use of a biopsy technique which allowed sampling before and after administration of digoxin. 3 Ten minutes after administration of digoxin the myocardial concentration increased from 60 to 306 nmol/kg tissue, the myocardial concentration of digoxin was significantly lower (250 nmol/kg tissue) after 30 min and then increased again. 4 The transmural myocardial distribution of digoxin was uniform before and 90 min after administration of digoxin in long-term digitalized dogs but at 10 min after administration, both the subepicardial and the subendocardial concentration of digoxin were significantly lower than that of the mesocardial layer. 5 During the first 10 min the dp/dtmax increased to 135% of the control level. The increase remained unchanged during the rest of the study. 6 Myocardial potassium decreased throughout the study. 7 The M-configuration of the myocardial uptake curve and the non-uniformity of myocardial distribution of digoxin observed at 10 min after administrating digoxin to long-term digitalized dogs indicate that the distribution of myocardial blood flow may be changed during chronic digitalization.

Myocardial digoxin uptake: dissociation between digitalis-induced inotropism and myocardial loss of potassium.

The time course of myocardial uptake of digoxin, of increase in inotropic effect and of changes in myocardial potassium content were studied following a single intravenous dose of digoxin. Nineteen dogs with intact circulation were investigated by the use of a biopsy technique which allowed samplings before and 10, 30, 60, and 90 min after administration of digoxin. The myocardial concentration of digoxin was 196 X 10(-9) mol/kg 10 min after administration of digoxin. Uptake continued at a slower rate, maximum concentration being 293 X 10(-9) mol/kg at 60 minutes. The inotropic effect increased parallel with the uptake of digoxin; 10 min after digoxin, contractility was 127% of the control value and this increased to 139% at 90 minutes. Myocardial potassium content was slightly increased 10 min after digoxin, suggesting an initial stimulation of membrane Na+-K+ ATPase. A subsequent significant fall in the myocardial potassium content probably reflects ATPase inhibition. The temporal dissociation between the early onset of the positive inotropic effect and the delayed inhibition of membrane Na+-K+ ATPase indicates that inotropism of digitalis glycosides is not mediated by the same binding site as that responsible for inhibition of Na+-K+ ATPase.

Time course of ouabain uptake in isolated myocardial cells: dependence on extracellular potassium and calcium concentration.

1 Spontaneously beating myocardial cells isolated from newborn rats have been used to evaluate the time course of cellular ouabain uptake. 2 The rate of cellular uptake and the amount of ouabain bound at equilibrium were computed by fitting the experimental data to the conventional exponential equation for receptor binding of drugs. 3 At normal extracellular potassium and calcium concentrations a biexponential equation was the best fit to the experimental data, indicating two receptor sites of ouabain with different rates of uptake. 4 Increasing extracellular potassium or calcium concentrations decreased the amounts of ouabain bound at equilibrium. 5 High and low extracellular concentrations of potassium or calcium decreased the rate of ouabain uptake. 6 It is well known that ouabain changes ionic fluxes. Changes in the extracellular potassium and calcium concentrations also influence the amount of ouabain taken up by myocardial cells, as demonstrated in the present study.

Doxorubicin binds in a cooperative manner to myocardial cells. Two binding sites.

Experimental evidence indicates that the anthracycline antibiotic doxorubicin (adriamycin) localizes mainly in cell nuclei of cardiac cells and has a high affinity to several cellular constituents in addition to DNA. In the present study the cellular kinetics of doxorubicin in cultured rat myocardial cells were determined by measuring its uptake, its binding pattern over a concentration range of 0.1 mM to 80 microM, and the cellular release by means of [14-14C]doxorubicin. The binding kinetics of doxorubicin were compared with the doxorubicin-induced inhibition of [methyl-3H]thymidine incorporation into DNA. It is demonstrated that at micromolar concentrations doxorubicin is readily taken up by myocardial cells and that myocardial cells have the ability to bind doxorubicin at two specific binding sites and that a noncooperative high-affinity/low-capacity type and a positive cooperative type of binding are involved, as indicated by the positive slope in the initial region of the binding isotherm (Scatchard plot). A dose-dependent inhibition of [methyl-3H]thymidine incorporation into DNA is demonstrated. It is suggested that this is associated with the positive cooperative binding of doxorubicin. The cellular release of doxorubicin appeared to be biphasic, with estimated half-lives of about 5-6 h for the initial phase and 50-60 h for the terminal phase. The results of this study indicate that doxorubicin preferably binds to sites within myocardial cells and that the positive cooperative binding pattern is due to DNA as one of the binding sites. A relationship between the noncooperative high-affinity/low capacity binding and the pharmacological activity has yet to be determined.

Similar changes in cardiac morphology and DNA synthesis induced by doxorubicin and 4'-epi-doxorubicin.

Doxorubicin is an antineoplastic agent whose clinical administration is limited by dose-dependent irreversible cardiomyopathy. Doxorubicin inhibits the rate of DNA synthesis in cultured rat myocardial cells after 1 h incubation with 16 microM, as is demonstrated by a decreased incorporation of [methyl-3H]thymidine. An analogue of doxorubicin, 4'-epi-doxorubicin, also inhibits the rate of DNA synthesis within 1 h after treatment with 16 microM, to the same extent as doxorubicin-treatment of myocardial cells. Furthermore, similarity between doxorubicin and 4'-epi-doxorubicin in their effect on the myocardial thymidylate pool was also demonstrated by a significantly decreased incorporation of total [methyl-3H]thymidine. The effect of doxorubicin on the rate of DNA synthesis in cultured rat skeletal muscle cells treated for 1 h with 16 microM was quantitatively the same as in myocardial cells. Light microscopy of doxorubicin- and 4'-epi-doxorubicin-treated myocardial cells and doxorubicin-treated skeletal muscle cells showed distinct nucleolar fragmentation and revealed no differences between the two drugs in their effect on either myocardial or skeletal muscle cells. Electron microscopy of myocardial cells following doxorubicin treatment showed increased nuclear pleomorphism and invaginations, along with a striking and distinctive clumping of nuclear chromatin. Furthermore, an apparent high density of the mitochondria due to an increased matrix volume and a concomitant decrease in the intermembrane compartment were observed. The results of this study indicate that doxorubicin-induced inhibition of cardiac DNA synthesis in cultured myocardial cells is nonpredictive of cardiotoxicity. The mechanism is at least bimodal, and the apparent minor toxicity of 4'-epi-doxorubicin compared with that of doxorubicin in clinical trials cannot be distinguished by a difference in the inhibition of DNA synthesis in the rat heart.

Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer.

Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m2. In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (mean t1/2 gamma, 21.6 +/- 7.9 h; range, 10.6-69 h; n = 110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (mean t1/2 gamma, 18.1 +/- 4.8 h; range, 8.2-38.4 h; n = 105). Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (mean t1/2 gamma, 13 +/- 4.6 h; range, 2.7-29 h; n = 104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC = 9.44 x c2 + 62.5 x c24 + 157.7 (r = 0.953).

Myocardial protection in coronary artery bypass surgery. A study comparing cold cardioplegia and intermittent aortic cross clamping.

Twenty patients having elective coronary artery bypass surgery were randomized for myocardial protection during cardiopulmonary bypass with cold cardioplegia and topical deep hypothermia with the Bretschneider solution in one group and intermittent aortic cross clamping at 30 degrees C in another group. The cardioplegic group showed more consistent results with lower CK-MB elevations both in terms of peak values and areas under the time-enzyme activity curves, although no statistical significance was obtained. There were significantly more infarct suspect time-enzyme activity curves in the intermittent cross clamping group (4 vs. O), and therefore, cold cardioplegia is advocated in preference to intermittent cross clamping in coronary artery bypass surgery.