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The influence of the serotonin antagonist ketanserin on the kinetics of digoxin and digitoxin were evaluated in healthy volunteers. Subjects received a single intravenous dose of digoxin (1.25 mg) or of digitoxin (1.0 mg) on two occasions: once in the control state, and again during treatment with ketanserin, 40 mg twice daily. Ketanserin caused a prolongation of digoxin elimination half-life (50 versus 40 h) and reduction in clearance (2.4 versus 3.7 ml/min/kg), but differences were not significant. For digitoxin, ketanserin caused a small but significant (p less than 0.005) increase in volume of distribution (0.89 versus 0.78 L/kg), but no significant effect on half-life (7.0 versus 6.8 days), or clearance (0.063 versus 0.059 ml/min/kg). Thus, ketanserin coadministration is not likely to alter steady-state concentrations of digoxin or digitoxin during clinical use of these two digitalis glycosides.

Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.

Some of the unwanted effects of quinidine commonly occurring in clinical practice involve the central nervous system. We therefore assessed the rate and extent of quinidine passage into cerebrospinal fluid (CSF) in humans and dogs. In eight human subjects receiving oral quinidine therapy, lumbar CSF quinidine concentrations averaged 16% of unbound serum concentrations (range: 4% to 37%). The findings were confirmed when simultaneous serum (total and unbound) and CSF quinidine concentrations were followed for up to 8 hours after a single intravenous dose of quinidine in anesthetized dogs. Quinidine appeared promptly in CSF of all animals, but CSF concentrations averaged only 37% to 46% of unbound serum levels. The in vitro octanol: water partition coefficient for quinidine at physiologic pH was greater than 100, indicating that unbound quinidine should readily traverse the blood-brain barrier. Thus, passage of quinidine into CSF appears not to be governed by passive diffusion alone. Quinidine may participate in an active transport system such as that which removes certain other basic substances from CSF.

The effects of Fab fragments of high-affinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10(10) M(-1) as determined by equilibrium dialysis. Rapid second-order association kinetics (k(f) = 3.7 x 10(6) M(-1) per s) and slow dissociation kinetics (k(r) = 1.9 x 10(-4) per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/kg digitoxin intravenously developed ventricular tachycardia after 23+/-4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+/-36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+/-3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+/-4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54+/-16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135 and 118 h by radioimmunoassay and [(3)H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t((1/2)) 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise lethal digitoxin toxicity, and are capable of reducing the plasma half-life and accelerating urinary excretion of digitoxin.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Five healthy volunteers received a single 0.5-mg dose of triazolam on two occasions: once with 100 to 200 ml of water, and on a second trial with 60 ml of commercial vodka mixed with 60 ml of water. There were no significant differences between control and ethanol-coadministration trials in peak serum triazolam level (5.4 vs. 5.4 ng/ml), time of peak level (1.5 vs. 1.6 hours), elimination half-life (2.8 vs. 2.6 hours), or apparent oral clearance (6.6 vs. 7.9 ml/min/kg). The potential pharmacodynamic interaction of triazolam and ethanol is more important than the minimal pharmacokinetic interaction.

Serum lidocaine concentrations were measured in a series of ten patients during and after topical lidocaine spray anesthesia used for diagnostic fiberoptic bronchoscopy. Mean total dose of lidocaine ranged from 480-720 mg. Peak serum lidocaine concentrations averaged 3.6 micrograms/ml (range: 1.9 to 7.4 micrograms/ml), and were attained shortly after the start of the procedure. Repeated topical administration of lidocaine spray therefore may lead to large cumulative doses and serum concentrations which are in the therapeutic or potentially toxic range.

12 Patienten, die mindestens fur zwei Tage mit Digoxin oder Beta-Methyldigoxin behandelt wurden, musten sich aus diagnostischen Grunden einer Lumbalpunktion unterziehen. Zur gleichen Zeit wurde eine venose Punktion durchgefuhrt. Das Plasma-Liquor-Konzentrationsverhaltnis betrug 2 fur Beta-Methyldigoxin und 8 fur Digoxin. Es scheint aber bisher nicht geklart, ob die starkere Anreicherung von β-Methyldigoxin im Liquor auch klinisch in einer hoheren Nebenwirkungsquote ihren Niederschlag findet.

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.

Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall means: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one-thirtieth that of the control value. Propranolol prolonged diazepam elimination t1/2 (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168-hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 micrograms/ml . hr). Propranolol had no significant effect on lorazepam t1/2 (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t1/2 (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction of N-demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.

Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=-0.36, p less than 0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS durations, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.