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Aims The influence of ageing on the pharmacokinetics of zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers. Methods A series of 16 elderly (age: 61–85 years) and 24 young (age: 22–42 years) volunteers received single 5 mg oral doses of zolpidem tartrate. Serum zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes. Results Among men, apparent oral clearance of zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min−1 kg−1, P

Sixteen normal healthy female volunteers, ages 22 to 42 years, participated in this study to determine the pharmacokinetic characteristics of zolpidem and the influence of oral contraceptives and smoking. Five of the volunteers were cigarette smokers, and 8 were on oral contraceptive preparations (OCP). All subjects received a 5 mg oral dose of zolpidem tartrate, followed by multiple blood samples that were assayed by HPLC with fluorescence detection. Among all subjects, mean apparent oral clearance was 376 ml/min (5.8 ml/min/kg), elimination half-life was 2.4 hours, and maximum serum zolpidem concentration was 60 ng/ml. Clearance was higher (445 vs. 345 ml/min) and half-life was shorter (1.8 vs. 2.7 h) in smokers than nonsmokers, although the differences were not statistically significant. Likewise, zolpidem clearance was higher and half-life shorter in women using OCP, but differences were not significant. Differences in zolpidem kinetics associated with smoking may be explained by the small contribution of cytochrome P450-1A2 to net clearance of zolpidem. In any case, the differences were quantitatively small and not likely to be of clinical importance.

The comparative effects of diltiazem and verapamil in 30 patients with long-standing atrial fibrillation were evaluated in a prospective clinical trial. After a one- to two-day washout period during which drugs other than digoxin were withdrawn, patients were randomly assigned to diltiazem or verapamil treatment groups. All therapy was double blind. Both drugs were given in ascending doses as follows: days 1-6 (part I): diltiazem, 180 mg/d, or verapamil, 240 mg/d; days 7-12 (part II): diltiazem, 360 mg/d, or verapamil, 480 mg/d. Patients failing to convert to sinus rhythm after 12 days had dosage reduced to 180 mg/d of diltiazem or 240 mg/d of verapamil, and quinidine, 750 mg/d, was coadministered for another six days (part III). Medication compliance was verified by frequent measurement of serum drug concentrations. Three verapamil patients dropped out during part I due to adverse reactions (dyspnea, pulmonary congestion, skin rash, or hepatotoxicity). The higher dosage of either verapamil or diltiazem in part II was not well tolerated, and in eight patients part III had to be initiated early due to symptomatic bradycardia. Only one patient in the diltiazem group converted to sinus rhythm, whereas five converted with verapamil (two with verapamil alone, three when combined with quinidine). Thus, diltiazem and verapamil alone are unlikely to convert atrial fibrillation to sinus rhythm. The combination of verapamil and quinidine, however, is a potentially useful pharmacologic approach, having converted atrial fibrillation to sinus rhythm in nearly 50% of patients.

Twelve healthy volunteers received a single 40-mg oral dose of the benzodiazepine derivative oxazolam, which serves primarily as a precursor of the active substance desmethyldiazepam (DMDZ). Concentrations of DMDZ were measured in multiple serum samples drawn for up to two weeks after the dose. Peak serum DMDZ concentrations averaged 115 ng/ml, measured at 8.6 hours after dosage. Mean DMDZ elimination half-life averaged 61 hours. Three of the subjects also received 40 mg each of prazepam and clorazepate, two other DMDZ precursors, on separate occasions. Although DMDZ elimination half-life was similar, total area under the curve (AUC) for DMDZ was larger for clorazepate, known to be completely transformed into DMDZ, than for oxazolam or prazepam the extent of whose conversion to DMDZ has not been previously established. After correcting for the different molar equivalent of DMDZ available from each preparation, the DMDZ ratio averaged 0.22 for oxazolam vs. clorazepate and 0.51 for prazepam vs. clorazepate. Thus, both oxazolam and prazepam lead to slow appearance of DMDZ in the systemic circulation. Furthermore the extent of DMDZ formation from oxazolam and prazepam is either incomplete or the drugs are incompletely absorbed. Equivalent doses of oxazolam, prazepam, and clorazepate should not be interchanged in clinical practice.

Normally menstruating young female volunteers with no evidence of cardiovascular disease participated in a controlled study of digoxin effects on serum thyroid stimulating hormone (TSH) and prolactin levels in the basal state and after stimulation with thyrotropin releasing hormone (TRH). In the first study, subjects received oral digoxin, 0.5 mg daily, or matching placebo, on days 10 through 22 of a menstrual cycle, then crossed over to placebo or digoxin for days 10 through 22 of the next cycle. Basal serum TSH and prolactin on days 7 through 9 and 20 through 22 did not differ significantly between placebo and digoxin cycles. Levels of both hormones rose after a 200-micrograms intravenous dose of TRH given on days 8 and 21, but the response to TRH did not differ between placebo and digoxin cycles. In the second study, subjects received 0.5 mg intravenous digoxin daily for days 7 through 21 of a menstrual cycle. Basal serum TRH and prolactin did not change significantly in response to digoxin. The findings suggest that hormonal changes associated with digoxin therapy, if they exist, are more likely to reflect direct effects on the target organ rather than indirect effects on the hypothalamic-pituitary axis.

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.

Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self-rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half-life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half-life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P less than .05). Self-ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

Healthy volunteers received a single dose of triazolam (0.5 mg) or oxazepam (30 mg) on two occasions, once in the control state and again during coadministration of isoniazid (INH) base, 180 mg day. INH coadministration prolonged triazolam half-life (3.3 vs 2.5 h, P less than 0.05) and increased total area under the curve (38.6 vs 26.5 ng ml-1 h, P less than 0.01) consistent with a reduction of apparent oral clearance (3.9 vs 6.8 ml min-1 kg-1, 0.05 less than P less than 0.1). INH coadministration had no influence on the kinetics of oxazepam. INH impairs hepatic microsomal oxidation of triazolam, leading to reduced first-pass hepatic extraction as well as prolonged half-life. However INH had no influence on oxazepam conjugation.

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)