H. C. Schoemaker

Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans

The effects of grapefruit juice (150 ml at −15, −10, ¼, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo‐controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)‐ and (R)‐nitrendipine. There were highly significant differences in the area under the concentration‐time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half‐lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.

A comparison of the sensitivities of adaptive tracking, eye movement analysis, and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers

The effects of single oral doses of 5, 10, and 20 mg temazepam were evaluated with the adaptive tracking test, analysis of smooth‐pursuit and saccadic eye movements, and visual analog lines in a placebo‐controlled, double‐blind, crossover experiment with 12 healthy volunteers. Pharmacodynamic testing was performed until 10 hours and pharmacokinetics were evaluated until 24 hours. Temazepam, 20 mg, caused effects in all tests, with peak effects occurring at 30 minutes. The 10 mg dose caused effects on saccadic eye movements and subjective scores of alertness, whereas 5 mg temazepam was detected only by analysis of saccadic eye movements. Linear relationships between plasma concentrations and effects were found in nine subjects for saccadic peak velocity and eight subjects for subjective scores of alertness. The results of this study demonstrate manifest differences in the sensitivities of performance tests and stress the importance of validation of methods when effects of drugs on human performance are studied.

The effects of clonazepam and vigabatrin in hyperekplexia

Hyperekplexia is an autosomal dominant disorder caused by a point mutation in the alpha1 subunit of the glycine receptor, characterized by excessive startle responses followed by temporary generalized stiffness. Clonazepam, effective in open case studies, potentiates, through unknown mechanisms, the neurotransmitter gamma-aminobutyric acid (GABA). Vigabatrin increases GABA by inhibition of the GABA catabolic enzyme GABA-transaminase. Effects of clonazepam (1 mg for 1 day) and vigabatrin (1000 mg per day for 5 days) were investigated in a double-blind placebo-controlled cross-over study in 4 patients with hyperekplexia. The pharmacodynamic parameters were startle reflexes, studied 3 times during the day. At each time, 2 trains of 10 auditive stimuli (113 dB) were given at intervals of 10 and 60 s. Startle movements were quantified with summed areas of EMG-bursts of the orbicularis oculi, sternocleidomastoid, biceps and thenar muscles. The degrees of stiffness and drowsiness were quantified with visual analogue scores (VAS) 10 times during the day, by both the patient and the observer. Clonazepam, but not vigabatrin, reduced startle activity significantly in both paradigms. The degree of stiffness and drowsiness was not significantly influenced by either drug.

Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state.

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2×2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24–0.57) after alcohol alone and 0.37 g/l (range: 0.27–0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol + diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.

Effects of temazepam on saccadic eye movements: Concentration‐effect relationships in individual volunteers

Saccadic eye movements were analyzed after single oral doses of 20 mg temazepam and placebo in a randomized, double‐blind crossover study in eight healthy volunteers. For an optimal evaluation of concentration‐effect relationships, 18 blood samples and 43 effect measures were obtained over 33½ hours. After placebo, saccadic peak velocity decreased within the first hour, with average values remaining 6.2% to 12.1% below baseline up to 15 hours after intake. After temazepam, significant changes in peak velocity occurred for 5 hours, with maximum decreases averaging 29.2% (95% confidence interval, 10.0 to 37.2). The apparent duration of effects ranged from 3 to 9 hours in individual subjects. Linear concentration‐effect relationships were demonstrated for peak velocity, with individual slopes ranging from −0.11 to −0.46 deg/sec · (ng/ml)−1 (average r = −0.82, all p < 0.01). Differences in protein binding of temazepam did not account for the approximate fourfold variability in individual sensitivities to temazepam. By increasing the frequency of measurements, the accuracy of pharmacodynamic evaluations was clearly enhanced in this study.

Highly variable anticoagulant response after subcutaneous administration of high-dose (12,500 IU) heparin in patients with myocardial infarction and healthy volunteers.

BackgroundIn this study, the anticoagulant response of 12,500 IU heparin s.c. was investigated in patients with myocardial infarction and healthy volunteers to determine variabilities in response and modifying factors. Methods and ResultsOn the fourth day after thrombolytic therapy, blood samples were taken before and at frequent intervals until 10 hours after the injection of 12,500 IU heparin s.c. Plasma anti-Xa activity, anti-Ha activity, and the activated partial thromboplastin time (APTT) were measured in addition to body weight and thickness of the abdominal subcutaneous fat layer. Contrary to expectations, the increase of anti-Xa activity, anti-lla activity, and APTT compared with baseline (predrug) levels was very small, with an average maximal APYIT of 42.6 seconds (SD, 12.4 seconds; range, 30.4–70.7 seconds). Subsequently, the influence of the length of the injection needle on the anticoagulant effect of 12,500 IU heparin s.c. was studied in 10 healthy volunteers to find a factor that could be responsible for the poor response in the patients. The length of the injection needle did not influence the anticoagulant effect of heparin. Large interindividual and intraindividual variabilities were seen in the volunteers. The majority of volunteers had minimal prolongation of the APWT, but very strong prolongation was also seen (maximal APIT, 163 seconds). There was no correlation between the abdominal skinfold thickness and anti-Xa activity, anti-Ha activity, or APTT (p>0.05), but in the patient study, there was a correlation between weight and anti-Xa activity and anti-Ila activity (p<0.05), and in the volunteer study, there was a correlation between weight and anti-Xa activity and APIT (p<0.05). ConclusionsSubcutaneous administration of heparin in a fixed dose for prophylactic and therapeutic purposes may be inadequate because of the large interindividual and intraindividual variations in anticoagulant effect.

Effects of intravenous temazepam. I. Saccadic eye movements and electroencephalogram after fast and slow infusion to pseudo steady state

To study the pharmacodynamic effects of intravenous temazepam after different infusion rates to pseudo steady‐state concentrations.

Specific stimulation of brain serotonin mediated neurotransmission by dexfenfluramine does not restore growth hormone responsiveness in obese women .

OBJECTIVE Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, using dl‐fenfluramine (dl‐FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect of dl‐FF appears to be dependent on the stimulus used to induce GH release. Furthermore, dl‐FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re‐uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d‐FF) affects the GH response to galanin or GHRH in obese subjects.

Effects of intravenous temazepam. II. A study of the long‐term reproducibility of pharmacokinetics, pharmacodynamics, and concentration‐effect parameters

To evaluate the long‐term reproducibility of pharmacokinetic, pharmacodynamic, and concentration‐effect parameters after intravenous administration of temazepam.

Plasma Amino Acid Ratios Related to Brain Serotonin Synthesis in Response to Food Intake in Bulimia Nervosa

Fifteen bulimic women (BN) and 19 healthy female controls (CO) were studied. The subjects were cross-over treated with either fluoxetine (FXT) or placebo during 4 days. They received, in randomized order, a breakfast containing pure carbohydrate (CHO) or a protein-rich (PROT) breakfast following day 3 and 4 of each treatment period. Twenty-nine different food items were offered for lunch. The fasting serum glucose and insulin concentrations and the fasting plasma tryptophan (Trp)/large neutral amino acid (LNAA) ratio were slightly higher in BN. The changes of these metabolic parameters in response to a CHO or PROT breakfast were similar in both groups. Across breakfast type, the plasma (Trp)/(LNAA) ratio at 120 min after breakfast was higher in BN. Total caloric intake at lunchtime was less in BN. In CO, less carbohydrate was selected at lunchtime following the CHO breakfast, an effect that was abolished by FXT. Breakfast type or FXT did not have any apparent effect on food intake at lunchtime in BN. This might indicate that bulimic subjects are less sensitive to serotoninergic stimuli than control subjects.