Comparative Study of the Absorption,Plasma Levels,and Urinary Excretion of the “New” and the “Old” Lanoxin

A comparative study was performed of the absorption, the plasma level at equilibrium, and the urinary excretion of digoxin using two types of Lanoxin tablets, those produced before and after the 1972 alteration of the tablet manufacture.After a single dose the absorption rate of the new tablets was about twice as great as the old, both in young subjects and in the elderly patients. There were no significant differences in the plasma levels of digoxin for the two tablets 15 hours after the last administration in patients on an equal maintenance dose. The urinary excretion of digoxin increased about 40% when the “old” Lanoxin was replaced by the “new.” In elderly patients a daily dose of 0·125 mg twice daily of the new tablets should be sufficient to reach the therapeutic range. Young people need a higher dosage. If the kidney function is reduced by as much as 50% the dose should be reduced.     

Effect of triamterene on leucocyte sodium and potassium levels in heart disease.

Sodium and potassium levels in plasma and leucocytes and the sodium efflux rate constants of leucocytes were measured in patients with congenital heart disease not on treatment, patients with valvular heart disease being treated with digoxin and conventional diuretics, and patients with valvular heart disease receiving digoxin and either conventional diuretics or triamterene or both. The group being treated with digoxin and conventional diuretics showed low cellular potassium levels, low sodium efflux rate constants, and a rise in cellular sodium levels. Patients given triamterene showed a rise in potassium levels in plasma and cells and in the sodium efflux rate constant.     

Large-scale Digitoxin Intoxication

Because of an error in the manufacture of digoxin tablets a large number of patients took tablets that contained 0·20 mg. of digitoxin and 0·05 mg. of digoxin instead of the prescribed 0·25 mg. of digoxin. The symptoms are described of 179 patients who took these tablets and suffered from digitalis intoxication. Of these patients, 125 had taken the faultily composed tablets for more than three weeks. In 48 patients 105 separate disturbances in rhythm or in atrioventricular conduction were observed on the electrocardiogram. Extreme fatigue and serious eye conditions were observed in 95% of the patients. Twelve patients had a transient psychosis. Extensive ophthalmological observations indicated that the visual complaints were most probably caused by a transient retrobulbar neuritis.     

Biological Availability of Digoxin from Lanoxin Produced in the United Kingdom

Though established quality control standards were maintained, the bioavailability of digoxin from Lanoxin tablets produced in the United Kingdom fell in 1969, and was restored in 1972. After 1·5 mg doses of representative batches, tablets made between 1969 and 1972 produced mean values for area under the 50 hours plasma concentration/time curve of 36·6 ng/ml/hr and four-day urinary excretion of 340 μg, compared with respective values of 67·5 ng/ml/hr and 696 μg for recently produced tablets.After 0·5 mg doses of four recent independently produced batches of Lanoxin tablets no significant between-batch difference was found for area under the plasma concentration/time curve or cumulative urinary excretion.Absorption of digoxin from batches of Lanoxin manufactured since May 1972 is uniform and consistent. Content uniformity is an inadequate measure of tablet quality, and consistent digoxin bioavailability cannot be ensured by existing regulations.     

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.     

Characterization of oral sustained release preparations of iloprost in a pig model by plasma level monitoring.

Iloprost (5-[(E)-1S,5S,6R,7R)-7-hydroxy-6-[(E)-3S,4RS)-3-hydroxy-4- methyl-octen-6-inyl]-bicyclo[3.3.0]-oct-3-ylidene)-pentanoic acid) is a chemically stable PGI2-mimetic with high pharmacological potency. Therapeutic efficacy in various disease stages (e.g. peripheral arterial occlusive disease, M. Raynaud and thromboangiitis obliterans) was shown after repeated once-a-day infusion treatment over several weeks. In order to facilitate drug therapy an oral dosage form is desirable. As a first step, a suitable animal model was needed to screen several formulation variants prior to characterization of promising candidates in man. After intravenous infusion treatment, the pig exhibited - similar to man - strictly dose-dependent steady state plasma levels and a total iloprost clearance of approximately 26 ml/min/kg (man approximately 20 ml/min/kg). Partial similarity of physiology and anatomy of the GI-tract and the possibility to administer intact capsule dosage forms led to a series of screen experiments with several sustained release preparations (pellets and matrix tablets) of iloprost exhibiting different in-vitro drug release profiles. A good correlation of in-vitro dissolution and in vivo plasma level data was obtained for all preparations containing the pellet neutral polymer. For the other formulations slight differences between duration of liberation and plasma level or time of maximum dissolution rate and tmax of plasma levels was observed. In the case of ionized polymers or matrix tablets, in vitro dissolution profiles were slightly different from in vivo data. This might be due to different dissolution behaviour in the gastro-intestinal tract. The pig seems to be a model that is suitable for verifying drug liberation profile in-vivo. Based upon plasma levels obtained in animals, selection of a formulation for characterization in man can be made.     

Serum digoxin in patients with thyroid disease.

Serum digoxin concentrations were measured by radioimmunoassay in 17 hyperthyroid and 16 hypothyroid patients after a seven-day course of oral digoxin. The significantly higher levels of serum digoxin in patients with hypothyroidism and lower levels in those with hyperthyroidism were closely related to the measured changes of glomerular filtration rate and digoxin serum half time in these two groups. Differences in serum digoxin concentration contribute to the altered sensitivity to digoxin shown by patients with thyroid disease.     

Rates of Dissolution of Tolbutamide Tablets

An investigation was made of the pharmaceutical properties and the in vitro dissolution rates of 18 commercially available brands of tolbutamide tablets, all of which met the limits set by the Food and Drug Regulations for tablets sold in Canada.A marked variation in dissolution rates was found, which bore no relation to the official disintegration time. These wide variations in dissolution rate point to a need for (a) a comprehensive study of the in vivo effects of different tolbutamide tablets, and (b) an official test that sets limits for the rate of dissolution of tolbutamide tablets, in addition to the one that places limits on disintegration time.     

Effect of Dosage Form Properties on Therapeutic Efficacy of Tolbutamide Tablets

The rate of gastrointestinal absorption and the physiologic availability of tolbutamide are functions of the dissolution rate of the drug in gastrointestinal fluids. This property can be modified markedly by pharmaceutical formulation factors. The in vitro dissolution rates of clinically efficacious and clinically inefficacious tolbutamide tablets have been determined, and it has been found that the former dissolved considerably more rapidly than the latter. Once diabetic patients have been “titrated” with a particular brand of tolbutamide they should not be switched to a different brand without “retitration.” There is need to establish an adequate in vitro test to assure the physiologic availability of tolbutamide from commercial tablets.     

Long-term digoxin treatment in general practice.

A questionnaire was sent to several general practitioners and specialists in an attempt to obtain a consensus on standards of care for patients receiving long-term digoxin treatment. The consultants'' suggested standards were slightly more stringent than those of the general practitioners. The records of 42 patients taking digoxin under the care of two general practitioners were studied to see how far their actual care matched up to the suggested standards. The models of management proposed by these patients'' doctors were only slightly different from those suggested by other practitioners, but measured against these models the patients'' care was in some cases inadequate. Nevertheless, there was little relationship between the recorded levels of care and the health of the patient, and it may have been the standard of recording rather than the care that was inadequate. Measuring plasma digoxin levels in these patients proved to be of little value. Medical audit is thus a useful tool in helping the general practitioner to review his work and improve his knowledge, but it may not be a practical or true way of measuring the quality of care.     

Comparative in vitro and in vivo evaluation of matrix,osmotic matrix,and osmotic pump tablets for controlled delivery of diclofenac sodium

The aim of this investigation was preparation and comparative evaluation of fabricated matrix (FM), osmotic matrix (OM), and osmotic pump (OP) tablets for controlled delivery of diclofenac sodium (DS). All formulations were evaluated for various physical parameters, and in vitro studies were performed on USP 24 dissolution apparatus II in pH 7.4 buffer and distilled water. In vivo studies were performed in 6 healthy human volunteers; the drug was assayed in plasma using HPLC, and results were compared with the performance of 2 commercial tablets of DS. Various pharmacokinetic parameters (ie, C_max, T_max, area under the curve [AUC_0–24], and mean residence time) and relative bioavailability were compared. All fabricated formulations showed more prolonged and controlled DS release compared with commercial tablets studied. The OM and OP tablets, however, performed better than the matrix tablets. The rate and extent of drug release from FM1 matrix tablets (single polymer) was significantly different from that of FM2 (admixed polymers). Type of porosigenic agents and osmogens also influenced the drug release. Analysis of in vitro data by regression coefficient analysis revealed zero-order release kinetics for OM and OP tablets, while FM tablets exhibited Higuchi kinetics. In vivo results indicated prolonged blood levels with delayed peak and improved bioavailability for fabricated tablets compared to commercial tablets. It was concluded that the osmotic matrix and osmotic pump tablets could provide more prolonged, controlled, and gastrointestinal environmental-independent DS release that may result in an improved therapeutic efficacy and patient compliance.     

Mechanisms of digoxin-amiodarone interaction in the rat

Amiodarone and digoxin are often used in combination and clinical experience suggests that amiodarone may increase serum digoxin levels and toxicity. We have investigated the influence of amiodarone on digoxin pharmacokinetics and tissue distribution in the rat. Forty-nine rats were injected with 10 mg/kg amiodarone sc three times a day for 7 days, while 49 others were injected with saline only. On the eighth day, all the rats received 0.5 mg/kg digoxin ip; 4, 5, 6, 7, 8, 10, and 12 hr later, groups of 7 amiodarone-pretreated and control animals were sacrificed, and plasma, heart, liver, muscle, brain, and kidney digoxin concentrations measured by radioimmunoassay. Data were analyzed by two-way ANOVA, with group comparisons using the Waller-Duncan multiple comparison procedure. Digoxin levels were significantly higher in the plasma, heart, muscle, and kidney of the amiodarone-pretreated rats at most points of measurement (P less than 0.05) whereas liver digoxin levels were elevated at 8, 10, and 12 hr. Kidney/plasma, heart/plasma, muscle/plasma, and especially liver/plasma ratios in the control groups significantly exceeded the values found in the amiodarone-pretreated group at most time points. Concentrations of digoxin in brain were not changed. This suggests that the volume of distribution is significantly altered in the amiodarone-pretreated group. Amiodarone increases plasma digoxin levels in rats as it does in humans, but the mechanism is unclear.     

Comparative effects of different cellulosic-based directly compressed orodispersable tablets on oral bioavailability of famotidine

Famotidine is a potent H₂-receptor antagonist most commonly used by elderly patients. Orodispersible tablets (ODT) are gaining popularity over conventional tablets due to their convenience and suitability for patients having dysphagia. The purpose of this study is to prepare famotidine ODT using the economic direct-compression method.A 3² full factorial design was used to evaluate the influence of different excipients on the properties and in vitro dissolution of famotidine ODT. Two factors were studied for their qualitative effects, namely, disintegrants and diluents. Disintegrants were studied in three levels viz. Ac-Di-Sol, sodium starch glycolate (Primojel) and low-substituted hydroxypropyl cellulose (L-HPC). Fillers were studied in three levels viz. mannitol, spray dried lactose and Avicel PH 101. The ODTs were prepared by direct compression and were evaluated for hardness, drug content, uniformity of weight, in vitro disintegration time, oral disintegration time, wetting time and in vitro dissolution. Maximum dissolution and minimum oral disintegration time (11.4 s) were observed in F7 prepared using L-HPC and mannitol. Furthermore, in human volunteers it showed significant increase in bioavailability compared to Servipep^® with mean AUC_(0–∞) 117.1 ng/ml and 82.71 ng/ml, respectively, and its relative bioavailability was 141.57%. Hence, ODT (F7) could possibly be used to overcome the drawbacks of conventional famotidine tablets in elderly patients with significant increase in oral bioavailability.     

Exercise heart rates at different serum digoxin concentrations in patients with atrial fibrillation.

Heart rate at rest and during increasing workloads was measured in a double blind study of 12 patients with chronic atrial fibrillation when serum concentrations of digoxin were nil and at low and high therapeutic values. Twelve normal subjects were studied for comparison. The heart rate at all levels of exercise in most patients with atrial fibrillation was not adequately controlled by any serum digoxin concentration tested despite a reduction in heart rate with increasing serum digoxin concentrations. Control of the resting heart rate, even in patients with high serum digoxin concentrations, did not ensure adequate control of the heart rate during work rates equivalent to regular daily activities.     

Correlating Cellulose Derivative Intrinsic Viscosity with Mechanical Susceptibility of Swollen Hydrophilic Matrix Tablets

Hydrophilic matrix tablets are prone to mechanical stress while passing through the gastrointestinal tract, which may result in inappropriate drug-release characteristics. Intrinsic viscosity is a physical polymer property that can be directly compared across various types and grades of polymers and correlated with the mechanical susceptibility of swollen matrix tablets. Five tablet formulations containing different HPMC and HPC polymers were prepared and analyzed using an in vitro glass bead manipulation test. The dissolution rate results were modeled using the Korsmeyer-Peppas equation and a correlation was found between the fit constants k and n, goodness-of-fit measure parameters, and intrinsic viscosity. Moreover, the dissolution profiles were used to calculate the degree of mechanical susceptibility for each formulation, defined as the ratio of the average dissolution rate after manipulation and the initial dissolution rate before manipulation. It was confirmed that an increased intrinsic viscosity polymer value resulted in a decrease in mechanical susceptibility. Considering this, two simple rules were defined for designing robust matrix tablets with respect to mechanical stresses.     

Myocardial and Skeletal Muscle Concentrations of Digoxin in Patients on Long-term Therapy

The digoxin content was measured in samples of left ventricular papillary muscle, skeletal muscle, and plasma obtained during mitral valve replacement from eight patients on maintenance treatment with the drug. The content in papillary muscle ranged from 15·5 to 132 ng/g (mean 77·7) and in skeletal muscle from 7·5 to 23 ng/g (mean 11·3). The ratio of myocardial digoxin concentration to plasma concentration varied between patients from 39:1 to 155:1. No simple relationship exists between plasma levels of digoxin and its concentration in the heart muscle, but total myocardial concentration may not accurately reflect therapeutic activity.     

Effect of hydroxypropyl methylcellulose and hydrogenated castor oil on naproxen release from sustained-release tablets

The effect of the concentration of hydrophilic (hydroxypropyl methylcellulose [HPMC]) and hydrophobic (hydrogenated castor oil [HCO]) products, fillers (lactose and dibasic calcium phosphate), and buffers (sodium bicarbonate, calcium carbonate, and sodium citrate) on naproxen release rate was studied. Matrix tablets were prepared by double compression, andIn vitro dissolution tests were performed. The dissolution results showed that an increased amount of HPMC or hydrogenated castor oil resulted in reduced drug release. The inclusion of buffers in the HPMC matrix tablets enhanced naproxen release. For HCO tablets, only sodium bicarbonate enhanced naproxen release. The presence of lactose on HPMC matrix tablets did not show a significantly different result from that obtained with the formulation containing dibasic calcium phosphate as a filler. However, for the tablets containing HCO, the presence of lactose significantly enhanced the naproxen release rate. The matrix-forming materials in this study were suitable for use in sustained-release tablets containing naproxen. The drug release can be modulated by adding suitable amounts of diluents and buffers.     

Behavior of the plasma level of digoxin in the rat in induced experimental hyperreninemia]

PRA, plasma and urine aldosterone levels and plasma digoxin were measured in rats in which digoxin had been administered under conditions of high PRA and high aldosterone levels experimentally induced by administering distilled water load and in rats in which digoxin had been administered without distilled water load. Results show that under conditions of high PRA and high aldosterone levels, plasma digoxin concentrations as measured 6 h after treatment were higher (45,3%) than in rats having received digoxin without water load. In assays carried out on rats sacrificed 12 h after digoxin treatment (with or without water load) all values approach basic levels again, thus suggesting that in rats too aldosterone might compete with digoxin at the level of tubular excretion.     

Plasma Concentrations of Digoxin after Oral Administration in the Fasting and Postprandial State

After the oral administration of 0·5 mg of digoxin in tablet form to fasting subjects peak plasma levels were reached in 30 to 60 minutes. Levels then fell to reach a plateau at six to eight hours. When the same dose was given after food the peak plasma concentrations were significantly lower, but the concentrations reached in samples obtained from two to eight hours after the dose did not differ appreciably from corresponding samples obtained in the fasting experiments.In a four-week cross-over study of 21 patients on maintenance therapy, digoxin taken regularly in the fasting state produced plasma concentrations similar to those obtained when the drug was taken after meals.The rapid appearance of digoxin in the blood suggests that the oral route of administration is adequate for most patients who require rapid digitalization, and the timing of maintenance dosage in relation to meals is unimportant.