Ingrid W. Reimann

Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man

SummaryThe pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (<0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.

Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolam-treated group.

Opipramol, a drug widely prescribed in Germany, is a tricyclic compound with no reuptake-inhibiting properties. However, it has pronounced D2-, 5-HT2-, and H1-blocking potential and high affinity to sigma receptors (sigma-1 and sigma-2). In early controlled trials, anxiolytic effects were revealed. However, those studies were performed before the concept of generalized anxiety disorder (GAD) was established. Because of the interesting receptor-binding profile and promising results of the early clinical trials, the authors performed a state-of-the-art placebo-controlled trial using alprazolam as an active control. Three hundred seven outpatients with GAD were included. After a 7-day single-blind placebo washout, patients were randomly assigned to receive either opipramol (final dose, 200 mg/day), alprazolam (2 mg/day), or placebo and were treated for 28 days. The efficacy of both active compounds was higher than the effects with placebo treatment. There were statistically significant differences (p < 0.05, according to the analysis of co-variance) in the main outcome criterion (baseline-adjusted final means of an intent-to-treat analysis of the total scores on the Hamilton Rating Scale for Anxiety) and in secondary efficacy parameters, with global improvement of 47% for placebo and significantly more for opipramol (63%) and alprazolam (64%). Regarding safety and tolerability, no substantial differences in the number of adverse events observed between treatment groups were obvious. Sedation seemed more pronounced with alprazolam treatment than with opipramol or placebo. In this trial, it was demonstrated for the first time that opipramol, a strong but nonselective sigma site ligand, possesses anxiolytic efficacy superior to placebo in the treatment of GAD.

Effects of diclofenac on lithium kinetics

The influence of the prostaglandin (PG) synthesis‐inhibiting, nonsteroidal anti‐inflammatory drug (NSAID) diclofenac on lithium kinetics was studied in five normal women on a 150‐mEq sodium diet. Diclofenac decreased lithium renal clearance by 23% (P = 0.002) and increased lithium plasma levels by 26% (P = 0.001). Renal PG synthesis was suppressed by 53% of control values. These data show a clinically important drug interaction, possibly on the basis of a PG‐dependent mechanism, with the risk of lithium intoxication for patients treated with lithium salts and NSAIDs.

Pharmacodynamic Interaction Between Midazolam and a Specific Benzodiazepine Antagonist in Humans

The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15–1788 has been investigated in six healthy male volunteers. Hypnotic steady‐state concentrations of midazolam (55 ± 11 ng/mL; mean ± SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two‐hour control period, the antagonist (2.5 mg) or the solvent were injected double‐blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight‐hour trial (Clearance = 670 ± 96 mL/min) concentrations of Ro 15–1788 declined rapidly with an elimination half‐life between 0.7 and 1.8 hours and a total plasma clearance of 702 ± 235 mL/min. Concentrations of Ro 15–1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15–1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15–1788. In conclusion, a small intravenous bolus of 2.5 mg Ro 15–1788 reverses rapidly the hypnotic action of midazolam. The relative short duration of the antagonistic effect is due to the fast hepatic elimination of Ro 15–1788, which might be a suitable antidote of benzodiazepine‐induced oversedation in special clinical situations.

Identification of the major metabolite of prostacyclin and 6-ketoprostaglandin F1α in man

Abstract Human volunteers were infused with 3 H- and 2 H-labeled prostacyclin or 3 H-labeled 6-ketoprostaglandin F 1α and, in separate experiments, with the unlabeled prostanoids. The urine was purified by different chromatographic steps and finally separated into several fractions by high-performance liquid chromatography. The major fractions contained 20.5 and 23.0% of the eluted radioactivity for the metabolites of prostacyclin and 6-ketoprostaglandin F 1α , respectively. The structure of both metabolites was identified by gas-liquid chromatography-mass spectrometry as dinor-6-ketoprostaglandin F 1α . It is concluded that the major metabolite of prostacyclin and 6-ketoprostaglandin F 1α in man is dinor-6-ketoprostaglandin F 1α .

Chronopharmacokinetic Study with Prolonged Infusion of Midazolam

SummaryPhysiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choke reaction time.In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent.Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.

Pharmacokinetics of ketanserin in man.

SummaryKinetic data for the new antihypertensive agent ketanserin were determined in six healthy subjects after single oral (40 mg) or intravenous (0.15 mg/kg) doses. Plasma protein binding was 94.0±1.8% (mean±SD). Cumulative urinary excretion of unchanged drug was less than 4% within 48 h following the single dose. The maximal plasma level (cmax) of 193±98.2 µg/l occured within 0.5 to 4.0 h after oral intake. The ketanserin plasma level declined biexponentially after oral administration, and triexponentially over the 36 h following intravenous injection. The terminal elimination half-life (term. t1/2) averaged 12.4±2.9 h and 12.8±4.8 h following oral and intravenous application, respectively. Total plasma clearance was 410±62.0 (i.v.) and 829±228 ml/min (p.o.) and the intravenous blood clearance averaged 602±91 ml/min, which indicates partly flowdependent hepatic elimination. A substantial first-pass effect led to a bioavailability of about 50% (range: 27–69%). Hepatic clearance of ketanserin followed the non-restrictive pattern. No change in blood pressure or heart rate was observed following ketanserin administration to normal volunteers.

Effects of cimetidine and ranitidine on steady‐state propranolol kinetics and dynamics

The influence of cimetidine (1000 mg daily, one day oral pretreatment) and ranitidine (300 mg daily by mouth, 1 and 6 days pretreatment) on steady‐state propranolol (160 mg sustained‐release capsule, once daily) plasma levels (Psss) and dynamic β‐blocker effects was assessed by bicycle ergometer exercise and isoproterenol sensitivity test in five normal subjects. During the 3 hr of the dynamic tests Psss were elevated from 25% to 67% by cimetidine, whereas Pss was unchanged by ranitidine. The estimated hepatic blood flow (EHBF) as calculated from indocyanine green (ICG) plasma clearance was only slightly reduced by 15 ± 23% (mean ±SD, n = 4) after one oral dose of 150 mg ranitidine and showed substantial intersubject variability. Dynamic parameters, like propranolol‐induced heart rate and blood pressure changes under physical exercise or during the isoproterenol sensitivity test, were not influenced by ranitidine or Cimetidine. Since our study was performed on normal subjects with relatively low propranolol doses these results do not rule out the risk of severe reinforcement of beta‐adrenergic receptor blocking effects if propranolol and cimetidine are taken together by patients.

Elevation of steady‐state diazepam levels by cimetidine

The effect of cimetidine (1000 mg/day) on steady‐state diazepam (5 mg/day) kinetics was investigated in six healthy subjects. During placebo‐controlled treatment for 11 days, trough steady‐state plasma levels were 130 ± 33 ng/ml and steady‐state concentration averaged 185 ±57 ng/ml (x̄ ± SD). During concomitant treatment with diazepam and cimetidine these concentrations rose to 194 ± 52 ng/ml and 255 ± 46 ng/ml (P < 0.002). The 40% to 50% increase was due to reduction (P = 0.026) of total body clearance from 20.9 ± 9.5 ml/min (control) to 14.0 ± 3.0 ml/min (with cimetidine). Diazepam elimination half‐life was also prolonged (P = 0.02, from 39.5 ± 16.6 hr to 101 ± 58.1 hr) by cimetidine.

Drug interactions through binding to cytochrome p 450: the experience with h2-receptor blocking agents.

H2-receptor blocking agents, such as cimetidine, ranitidine or oxmetidine, are consumed in large amounts often together with a variety of other drugs. There is increasing evidence that cimetidine interferes with the hepatic elimination of several drugs, thereby aggravating the effects of the comedication. Microsomal studies in vitro revealed that cimetidine binds in therapeutic concentrations to cytochrome P450, which may represent the primary mechanism for its ability to inhibit drug metabolism and thereby interact with other drugs. The structurally different ranitidine (replacement of the imidazole in cimetidine by a furan ring) is about five times as potent as a H2-receptor blocker and displays low affinity for binding sites on cytochrome P 450. Therefore, therapeutic doses of ranitidine do not impair the metabolism of other drugs. Preliminary data with oxmetidine suggest that it too does not interfere at the level of hepatic elimination. Thus, it is concluded that new therapeutic agents should be tested for their ability to bind to cytochrome P 450 to determine possible risks of drug interactions.