Diltiazem increases steady state digoxin serum levels in patients with cardiac disease

Diltiazem has been reported to decrease or not to affect digoxin elimination. The effects of diltiazem on steady state concentrations of digoxin was evaluated in eleven patients with congestive heart failure receiving this drug for at least two weeks. The mean trough digoxin was 1.11 +/- 0.18 ng/ml before the coadministration of diltiazem (180 mg/day). This concentration increased to 1.54 +/- 0.22 ng/ml after three days and to 1.54 +/- 0.23 ng/ml after seven days of coadministration (P less than 0.01). Clinically, no patient showed signs of digitalis toxicity. Creatinine clearance was unchanged. The present results show that when diltiazem is added to a regimen that includes digoxin, steady state concentrations of this glycoside may increase.     

Comparison of medigoxin and digoxin in the control of atrial fibrillation.

1 Medigoxin (Lanitop) 300 microgram/day and digoxin (Lanoxin) 500 microgram/day were compared in cross-over studies on healthy volunteers and on patients with uncontrolled atrial fibrillation. Serum glycoside concentrations were measured by radioimmunoassay and ventricular rates by ECG. The two regimens appeared to be therapeutically equivalent. 2 The mean serum glycoside concentration in the steady state and the rate at which this state was attained were similar with both drug regimens in the healthy volunteer group. The between-subject variation in serum glycoside concentration was not significantly less during medigoxin administration. 3 The renal clearance of serum glycoside was much lower during medigoxin administration both in healthy volunteers and in patients. This was not due to a difference in serum protein binding. The relatively small dosage requirement for medigoxin was attributed partly to a lower clearance rate and partly to more nearly complete absorption. 4 During the first 2 weeks of the patient study there was a substantial rise in mean serum glycoside concentration and a corresponding fall in ventricular rate. This was attributed to more consistent self-administration of digoxin. The subsequent change to medigoxin had no further effect on mean glycoside concentration, ventricular rate or frequency of ventricular ectopic beats. 5. An attempt to compare the onset of the ventricular rate response to a single oral dose of medigoxin with that to digoxin gave inconclusive results.     

Interaction between digoxin and propafenone

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.     

Basic and clinical studies on clarithromycin in pediatrics

Clarithromycin (TE-031, A-56268) is a new macrolide antibiotic developed by Taisho Pharmaceutical Co., Ltd. Basic and clinical studies in the field of pediatrics were carried out on a granular preparation and 50 mg tablets of TE-031 designed for use in children. The following results were obtained. 1. Concentrations of TE-031 in the serum and its excretion in the urine were investigated in children. Six children were orally administered with a TE-031 granular preparation at 10 mg/kg in a cross-over study 30 minutes before meal and 30 minutes after meal. When the drug was ingested before meal, the mean peak serum concentration occurred 1 hour later and was 5.32 +/- 1.20 micrograms/ml. The mean half-life of TE-031 in the serum was 3.6 +/- 1.0 hours, and drug levels decreased to 1.94 +/- 0.55 micrograms/ml at 6 hours after dosing. In cases of the postprandial administration, the mean peak serum level was 4.21 +/- 1.25 micrograms/ml, occurring 2 hours after ingestion. The mean serum half-life in these cases was 3.5 +/- 1.3 hours, and serum levels decreased to 1.66 +/- 0.47 micrograms/ml at 6 hours after dosing. Mean urinary recovery rates during the initial 6 hours after ingestion were 30.5 +/- 6.4% in the cases of preprandial administration and 34.7 +/- 7.3% with postprandial administration. In addition, 30 minutes before meal, 50 mg tablets of TE-031 were orally administered to 3 children in a dose level equivalent to approximately 10 mg/kg, followed by monitoring of serum and urinary levels. It was found that the mean serum concentration showed a peak value of 4.10 +/- 0.44 micrograms/ml at 2 hours after dosing, the mean serum half-life was 3.5 +/- 0.7 hours, and the mean level fell to 1.90 +/- 0.55 micrograms/ml by 6 hours after dosing. The mean 6-hour urinary recovery rate was 32.7 +/- 12.1%. On the basis of the above results, it has been surmised that, in comparison to conventional macrolide antibiotics. TE-031 is better maintained in the blood at a high concentration and is more efficiently excreted into the urine. In addition, the data show that the bioavailability of TE-031 is slightly superior when the drug is administered on an empty stomach compared with after a meal. And finally, it was found that the granular and 50 mg tablet preparations of TE-031 are almost equivalent in terms of the absorption and the excretion of the drug.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of amiodarone on oral digoxin bioavailability in healthy volunteers

The aim of the present work was to evaluate the possible influence of amiodarone on some basic parameters of acute oral digoxin kinetics. A single oral dose of digoxin (0.50 mg) was administered to six healthy volunteers both before and at the end of a 7-day treatment with with amiodarone. This treatment caused a clear-cut rise in peak serum digoxin levels (Cmax) from 2.92 +/- 1.09 to 5.87 +/- 1.68 ng/ml (p less than 0.005) and a decrease of the peak time (Tmax) in four out of the six subjects. The area under the serum concentration-time curve (AUC) was increased by amiodarone with a high individual variability (30.71 +/- 6.15 vs 40.63 +/- 10.04 ng X h X ml-1). Also the 72-hour recovery of the glycoside in the urine was higher (258.77 +/- 68.41 vs 357.62 +/- 62.98 micrograms; p less than 0.01), while renal clearance (Clr) was not altered. These results show that amiodarone increases digoxin bioavailability by a mechanism which appears to be independent of changes in drug elimination.     

Antiarrhythmic effect of lorcainide in patients taking digoxin

To assess the antiarrhythmic effect of lorcainide and determine whether there is a pharmacokinetic interaction between lorcainide and digoxin, 12 patients with frequent premature ventricular depolarizations (PVDs) who were taking digoxin were treated with lorcainide. During a placebo period, serum digoxin concentration was measured for three days; plasma lorcainide concentration, a 12-lead electrocardiogram (ECG), and a 24-hour continuous ECG were measured on the day before the patients began lorcainide and repeated on days 3, 7, and 14 of treatment. Lorcainide was given 100 mg bid or 100 mg tid. Lorcainide did not suppress group mean PVDs per hour, pairs, or ventricular tachycardia. Only four patients (33%) responded with greater than or equal to 80% suppression of PVDs. Mean ejection fraction for responders was 46 +/- 6%, and for nonresponders it was 28 +/- 9% (P less than .01). There was no significant pharmacokinetic interaction between lorcainide and digoxin. Mean digoxin concentration did not change after lorcainide administration; two patients had greater than or equal to 50% increase in serum digoxin concentration. Patients with heart failure or reduced ejection fraction define a subset who have unpredictable effects from lorcainide, including a reduced antiarrhythmic effect.     

Influence of food on the absorption of flurithromycin in man

Oral absorption of flurithromycin, a new fluorinated macrolide, has been evaluated on eight healthy volunteers on fasting and after a standard meal. Serum levels from 0 to 8 hours, peak serum concentrations, times to peak and areas under the curves were compared using a balanced sequence cross-over design. The highest mean concentration was reached after 3 h from administration on fasting (1.36 +/- 0.31 mcg/ml) and after 1 h following a meal (1.36 +/- 0.30 mcg/ml). All the pharmacokinetic parameters considered showed no statistical change. Therefore a meal does not reduce or delay the absorption of flurithromycin, while in the presence of food other macrolides may behave differently. Moreover the tolerability to the drug was good, lacking any report of side-effects, either on fasting or after the food.     

The effects of captopril on serum digoxin levels in patients with severe congestive heart failure

The effects of captopril on serum digoxin concentrations were studied in 8 patients with severe (NYHA Class IV) congestive heart failure. Serum digoxin concentrations were determined before and after the administration of captopril for 1 week in patients on chronic digoxin therapy. Each patient who was taking 0.25 mg of digoxin PO q.d., was administered 12.5 mg of captopril PO t.i.d. for 7 days. The peak serum concentration of digoxin (Cmax) before and after (on Days 0 and 7) captopril administration was 1.7+/-0.2 ng/ml and 2.7+/-0.2 ng/ml, the time to peak (tmax) was 2.4+/-0.5 h and 1.3+/-0.2 h, and the area under the 24-hour digoxin concentration-time curve (AUC0-24h) was 30.0+/-1.5 ng x h/ml and 41.7+/-3.4 ng x h/ml, respectively. While captopril caused a significant increase in peak serum concentration and the area under the digoxin concentration-time curve, it decreased the time to digoxin peak (p = 0.01, p = 0.04, p = 0.01, respectively). No patient developed evidence of digoxin toxicity. Concomitant administration of captopril with digoxin increases serum digoxin concentration in patients with severe congestive heart failure.     

Bioavailability of digoxin tablets in healthy volunteers

The bioavailability of digoxin generic tablets manufactured in Korea (formulations A & B) were compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a Latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5 mg oral digoxin. Digoxin concentrations in serum and urine samples collected for 48 hours after dosing were measured by fluorescence polarization immunoassay and radioimmunoassay, respectively. Treatments were compared by using nonlinear least squares regression analysis to evaluate the following pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (Tmax); area under the serum concentration-time curve for 0-12 hours (AUC0-12); and cummulative urinary excretion for 0-48 hours (CUE0-48). Mean AUC0-12, Cmax, and CUE0-48 values for formulations B and C were significantly different from formulation A (p < 0.001), but not significantly different from each other. Based on AUC0-12 and CUE0-48, respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formulation A was 43% and 35% when compared to formulation C (the standard).     

Effect of food and various antacids on the absorption of tenoxicam.

1 Twelve healthy volunteers received a single oral dose of tenoxicam 20 mg on six occasions separated by 3 weeks. 2 The six occasions were: fasted overnight; postprandial; fasting and 15 ml aluminium hydroxide gel; postprandial and 15 ml aluminium hydroxide gel; fasting and 15 ml aluminium and magnesium hydroxide gel; postprandial and 15 ml aluminium and magnesium hydroxide gel. 3 Twenty plasma samples were collected over 15 days following dosing with tenoxicam. 4 The following kinetic parameters for plasma tenoxicam were compared: peak concentrations, time taken to reach peak concentrations, area under the plasma concentration-time curve (AUC) and half-life of elimination. 5 Food lengthened the time taken to reach peak tenoxicam concentrations (5.82 +/- 4.6 vs 1.84 +/- 1.0 h in the fasting state; P less than 0.02) and marginally reduced the peak concentrations achieved. AUC was not affected by any of the different regimens. 6 These effects of food on tenoxicam bioavailability are unlikely to be of clinical significance during chronic dosing with the drug.     

Effect of coadministration of verapamil and quinidine on serum digoxin concentration

Both quinidine and verapamil are known to increase the serum digoxin concentration (SDC), and other calcium channel blockers may have a similar effect. Since an increasing number of patients is likely to be treated concurrently with digoxin, quinidine and a calcium channel blocker, a study was done to show whether coadministered quinidine and verapamil would cooperate to elevate the SDC. Nine healthy volunteers on basic digoxin treatment (Leanoxin 0.125 mg t.i.d.) were treated with placebo, verapamil 80 mg t.i.d. and the combination (verapamil 80 mg plus quinidine base 160 mg t.i.d.), for 2 weeks in a randomized sequence. Drug concentration and various cardiovascular parameters were measured each week and/or at the end of each treatment period. Steady state concentrations were always obtained within 1 week and drug levels at the end of the first and second weeks of treatment were almost identical. The plasma verapamil concentration (PVC) was 25.8 +/- 9.9 ng/ml during coadministration of verapamil and digoxin, and 15.7 +/- 6.9 ng/ml during combined verapamil-quinidine coadministration, when the serum quinidine concentration (SQC) was 1.26 +/- 0.50 micrograms/ml. Compared to placebo SDC rose by 53% from 0.62 +/- 0.16 to 0.95 +/- 0.29 ng/ml (p less than 0.001) during verapamil treatment and further to 1.58 +/- 0.38 ng/ml (155% rise; p less than 0.001) during combined verapamil-quinidine coadministration. Thus each drug maintained its own effect on SDC in the presence of the other, and their actions became combined in increasing the SDC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of tiaprofenic acid on serum digoxin concentration

The effect of concomitant tiaprofenic acid (Surgam) administration (200 mg t.i.d.) on serum digoxin concentration (SDC) was evaluated in 12 healthy volunteers on digoxin maintenance treatment. During a 10-day coadministration period with tiaprofenic acid no significant increase in SDC was observed (0.97 +/- 0.24 vs. 1.12 +/- 0.21 ng/ml, p less than 0.05). Mean tiaprofenic acid concentration amounted to 2.85 +/- 1.94 micrograms/ml 14 h after last drug intake. The incidence of adverse reactions was minimal with gastrointestinal upset in one person. Tiaprofenic acid had no influence on red or white blood cell count. Thus, in contrast to various other nonsteroidal antiinflammatory drugs coadministration of tiaprofenic acid (600 mg daily) has no relevant influence on serum digoxin levels.     

Lack of effect of enoximone on the pharmacokinetics of digoxin in patients with congestive heart failure

The aim of this study was to investigate if the concomitant administration of the positive inotropic drug enoximone (100 mg tid) has any effect on the morning through levels of the cardiac glycoside digoxin in 17 patients with congestive heart failure (NYHA II-IV). Plasma concentrations of digoxin were 1.05 +/- 0.37 ng/mL before enoximone, 0.95 +/- 0.31 ng/mL at the end of the enoximone treatment period of 1 week and 0.95 +/- 0.36 ng/mL 1 week after cessation of enoximone treatment. Thus, concomitant administration of enoximone had no effect on plasma concentrations of digoxin while on the other hand the hemodynamics as assessed by NYHA-classification and determination of the heart volume improved significantly.     

Postprandial delay of drug absorption in a gitoformate model

Oral absorption of gitoformate (Dynocard), a non-renal-dependent cardiac glycoside, was investigated in 8 healthy subjects aged 23-45 years. Plasma concentration-time profiles were obtained once following a 12-h period of fasting, then after intake of a standard high protein meal. The half-life of absorption t1/2a, Cmax and tmax, half-life of elimination t1/2z, and area under the curve (AUC) were compared to evaluate the influence on the bioavailability of gitoformate. t1/2a in the fasting condition (0.36 +/- 0.43 h) is increased when gitoformate is applied after a high protein meal 1.12 +/- 1.12 h). Correspondingly, fasting maximum concentrations are already achieved after 1.4 +/- 1.2 h, but only after 4.8 +/- 1.8 h following the intake of a standard meal. Comparison of AUC (0-168 h) showed that the bioavailability was reduced by 25% after meals.     

Effect of somatostatin-14 on gastric emptying and on gastrin and insulin release after ingestion of a mixed solid-liquid meal in man

The effect of somatostatin-14 on gastric emptying, as well as on serum concentrations of gastrin, insulin, glucose, calcium, and phosphorus after ingestion of a mixed solid-liquid meal was examined in seven healthy men in a double-blind placebo-controlled study. An i.v. bolus injection of 61 nmol somatostatin was followed by 244 nmol infused at a constant rate over 90 minutes. Gastric emptying of a radiolabelled meal was surveyed with the use of a gamma camera. A weak delaying effect of somatostatin on gastric emptying of a solid meal did not prove to be statistically significant. Somatostatin decreased significantly the postprandial gastrin release: the area under the gastrin curve, AUC0-90, 9954 +/- 2287 ng.l-1 min (placebo) vs 5327 +/- 718 ng.l-1 min (somatostatin), p less than 0.05. At the same time suppression of the postprandial insulin release by somatostatin was observed--area under the insulin curve, AUC0-90, 1450 +/- 161 mU.l-1 min (placebo) vs 501 +/- 60 mU.l-1 min (somatostatin), p less than 0.002. The postprandial increase in serum glucose concentration was initially attenuated, and shifted towards the end of somatostatin infusion, when referred to the placebo situation. Somatostatin did not change significantly the serum calcium or phosphorus concentrations. The results obtained indicate that somatostatin's effect on gastric evacuation is less pronounced in contrast to the significant inhibitory influence of somatostatin on release of gastrointestinal hormones.     

Comparison of digoxin and medigoxin in normal subjects

1 The properties of a recently introduced digitalis glycoside, 4-beta-methyl digoxin (medigoxin) were compared to those of a standard digoxin preparation. Using a radioimmunoassay (RIA) technique, serial plasma levels were recorded for 8 h following a single oral dose in five fasting volunteer subjects, and urinary glycoside elimination was measured for 4 consecutive days after dosage by use of a modification of the RIA method. 2 It was found that this RIA was suitable for plasma level measurement of both digoxin and midigoxin by reference to appropriate standard curves. Comparison of the plasma level profiles of these two drugs showed that medigoxin was very rapidly absorbed with peak levels occurring within 15--30 min, while digoxin produced peak levels after 45--75 min. The area under the plasma level-time curve produced by medigoxin was also consistently greater than that produced by digoxin, even though the medigoxin dose used was smaller. Quantitative comparison of these areas after adjustment to compensate for differing doses showed that medigoxin is considerably more biologically available than digoxin under study conditions (ratio 1.6 +/- 0.25:1), and comparison of quantitative urinary elimination suggested that medigoxin is eliminated in the urine to a lesser extent than digoxin and therefore it undergoes more metabolism and/or hepato-biliary elimination.     

Studies on sultamicillin in the field of pediatrics

Pharmacokinetic and clinical studies on sultamicillin (SBTPC) were carried out in the field of pediatrics. 1. Absorption and excretion. A crossover study with a single oral administration of 10 mg/kg of SBTPC in fasting and after meal, and that with 10 mg/kg and 20 mg/kg of SBTPC after meal were carried out in 11 children (5-15 years) and in 6 children (8-15 years), respectively. Serum levels and urinary excretion of sulbactam (SBT) and ampicillin (ABPC) were determined. Mean serum concentrations of ABPC after oral administration of 10 mg/kg of SBTPC with in fasting or after meal, in the former study, peaked at 4.75 +/- 1.97 micrograms/ml in 1 hour and declined with a mean half-life of 0.81 +/- 0.18 hour and the mean serum concentration of ABPC at 6 hours after administration was 0.06 +/- 0.07 micrograms/ml. Mean serum concentration of ABPC study in the latter peaked at 2.95 +/- 0.79 micrograms/ml in 1 hour, and declined with a mean half-life of 1.35 +/- 0.43 hours, and the mean serum concentration of ABPC at 6 hours was 0.22 +/- 0.13 microgram/ml. Mean urinary recovery rates of ABPC in 6 hours after administration were 54.5 +/- 17.6% in the former study, and 63.2 +/- 14.3% in the latter. These results suggested a delay of absorption with meal. Mean serum concentrations of ABPC after oral administration of 10 mg/kg or 20 mg/kg of SBTPC after meal, in the former study, were 3.10 +/- 0.72 micrograms/ml at 1 hour and declined with a half-life of 1.22 +/- 0.32 hours, and those of ABPC were 0.22 +/- 0.12 microgram/ml at 6 hours, and they were 6.46 +/- 1.57 micrograms/ml, 1.48 +/- 0.51 hours and 0.55 +/- 0.40 microgram/ml, respectively in the latter study. Mean urinary recovery rates of ABPC in 6 hours, were 50.4 +/- 10.2% in the former study and 57.7 +/- 11.4%, in the latter. A dose response was observed with time course of mean serum concentrations. Mean serum concentrations of SBT were lower than those of ABPC, and they declined in a similar manner. The mean urinary recovery rate of SBT was similar or lower than that of ABPC. 2. Clinical study SBTPC was used for the treatment of a total of 38 pediatric patients with ages 6 months to 11 years and it's clinical effectiveness, bacteriological efficacy and adverse effects were evaluated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of food on the bioavailability of lisinopril, a nonsulfhydryl angiotensin-converting enzyme inhibitor

A randomized, two-way, crossover study was performed on 18 normal volunteers to assess the influence of food on the bioavailability of lisinopril, (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline), a long-acting nonsulfhydryl angiotensin converting enzyme inhibitor. A single, 20-mg oral dose of lisinopril was administered to volunteers in the fasting state or following a standardized breakfast. Treatment periods were separated by 2-week intervals. No significant differences existed between fasting and fed regimens in the mean +/- SD area under the serum concentration-time curve (AUC0-120h; 1231 +/- 620 versus 1029 +/- 254 ng X h X ml-1), peak lisinopril serum concentration (86 +/- 48 versus 69 +/- 19 ng/mL), or time to peak lisinopril serum concentration (6.2 +/- 1.1 versus 6.8 +/- 1.0 h). Five-day urinary excretion of lisinopril was not altered by food (5.3 +/- 3.0 versus 5.1 +/- 2.0 mg). Based on the urinary data, the mean +/- SD bioavailability of lisinopril was not different following fasting or fed regimens (27 +/- 15 versus 26 +/- 10%). Unlike with captopril, food did not affect the bioavailability of lisinopril.     

估算肾功能不全的心衰患者血清地高辛总浓度和地高辛样免疫活性物质浓度

用超滤-荧光极化免疫分析法测定血清地高辛游离浓度,结合其游离百分率,估算了12位伴有肾功能不全的慢性心衰患者血清地高辛总浓度和地高辛样免疫活性物质(DLIS)浓度。结果表明,患者的血清实测地高辛游离浓度为0.79±0.48nmol·L^-1;实测地高辛总浓度为1.31±0.80nmol·L^-1,明显高于计算的地高辛总浓度(1.05±0.64nmol·L^-1),P<0.01。计算的DLIS浓度为0.27±0.19nmol·L^-1,该结果与用Dasgupta等新近报道的计算方法获得的数据(0.29±0.22nmol·L^-1)一致(P>0.05)。     

Effects of foods on the pharmacokinetics and clinical efficacy of quazepam.

The effects of foods on the pharmacokinetics and clinical efficacy of quazepam, a benzodiazepine derivative, in healthy persons were examined. Six healthy Japanese male subjects were randomly divided into three groups and each subject was treated with quazepam under the following three conditions by the crossover method. For the fasting state, subjects were administered 15 mg quazepam 11 hours after a meal. For the postprandial state, subjects were administered 15 mg or 30 mg quazepam 2 hours after a meal. Mean peak plasma concentration (Cmax) of quazepam was significantly higher [1.6-2.8 fold] with administration 2 hours after a meal than 11 hours after a meal. However, in regard to 15 mg of quazepam administration, the area under the curve (AUC) did not differ between administration 2 hours after a meal and 11 hours after a meal. In addition, differences were observed neither in other pharmacokinetic parameters or blood metabolite concentration under all of the study conditions, nor in clinical evaluation of subjective symptoms, complete blood count, or biochemical analyses between administrations 2 and 11 hrs after a meal. The present study showed that administration 2 hours after a meal did not affect subjective symptoms or physical functions so much; therefore it suggested favorable tolerance of this drug. However, it was also suggested that, in actual clinical use, it is important to evaluate the physical function including measurements of vital signs and hematological test results, carefully considering the effects of foods and daily life-style.