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Biomedical subjects

I W Reimann

Publications and source records attributed to I W Reimann.

At least 19 recordsLinked to original sources
PubMed2001

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 covariance) 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.

Adolescent↗
PubMed1996

Different modes of data processing and statistical testing applied to the same set of pharmaco-EEG recordings: effects on the evaluation of a selective and reversible MAO A inhibitor (brofaromine).

The comparison of two different modes of data processing and two different approaches to statistical testing both applied to the same set of EEG recordings was the main objective of this pharmacological study. Brofaromine (CGP 11,305 A), a new selective and reversible monoamine oxidase type A inhibitor was used as an example for investigating a potentially antidepressant drug in clinical development. The two modes of pharmaco-EEG (PEEG) data processing differed mainly in the sampling frequency and definition of spectral parameters. Patterns of significant changes were noted in terms of descriptive data analysis using either a nonparametric Wilcoxon signed-rank test or an ANOVA of transformed data, as suggested by Conover and Iman. These data clearly demonstrate that slight discrepancies in the results may simply arise from differences in data processing and statistical approach applied. In spite of these discrepancies, the pattern of brofaromine-induced PEEG changes was very similar regardless of the mode of data handling used.

Adult↗
PubMed1993

Oxaprotiline: enantioselective noradrenaline uptake inhibition indicated by intravenous amine pressor tests but not alpha 2-adrenoceptor binding to intact platelets in man.

The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (-) oxaprotiline CGP 12,103 A (levoprotiline) and the S (+) oxaprotiline CGP 12,104 A, have been used as tools for a methodological Phase I study. Only the S (+) enantiomer CGP 12,104 A inhibits noradrenaline uptake. Intravenous amine pressor tests and ex vivo measurement of alpha 2-adrenoceptor binding to intact human platelets were compared with respect to their reliability in indicating CGP 12,104 A-induced amine uptake inhibition and possibly associated alpha 2-receptor down-regulation in healthy subjects. alpha 2-Adrenoceptor binding on intact human platelets did not distinguish between CGP 12,104 and CGP 12,103 A. However, amine pressor tests reflected the amine uptake inhibiting effect of CGP 12,104 A as a 5-fold decrease in tyramine pressor sensitivity and a 5-fold increase in noradrenaline pressor sensitivity.

Adult↗
PubMed1992

Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers.

To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two-way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (= total levoprotiline) were determined by a specific gas chromatographic-mass spectro-metric method. Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady-state volume of distribution was 18.81 kg-1. The elimination of levoprotiline from blood was independent of the dosing route, the half-life being 18.8 h. Only 1.8 and 0.6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline. The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first-pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min-1, the renal blood clearance after i.v. and p.o. dosing was only 16.0 and 14.2 ml min-1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.

Administration, Oral↗
PubMed1992

Intravenous amine pressor tests in healthy volunteers. Within- and between subject variances and sex differences.

The pressor effect of intravenous tyramine (TYR) and noradrenaline (NA) has been evaluated, respectively, in 157 tests in 19 healthy unmedicated subjects, and in 202 tests in 24 similar subjects, all of whom took part in greater than or equal to 3 test sessions. The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for TYR, and from 3.5 to 17 micrograms.min-1 for NA. Coefficients of variation ranged from 3 to 47% and from 6 to 38% for TYR and NA, respectively, in the intra-subject comparison. The average inter-subject variation in the TYR PD30 was 22% for 8 females and 30% for 11 males; the corresponding variation in the NA PD30 was 27% (8 females) and 26% (16 males). While the average PD30 for NA was similar for males (10.8 micrograms/min) and females (10.9 micrograms/min), a sex-related difference was found for the PD30 of i.v. TYR: 4.4 mg for 11 males and 3.8 mg for 8 females. Additional results from volunteers who took part in fewer than 3 pressor test sessions supported this observation; PD30 of TYR 4.6 mg in 34 males vs 3.5 mg in 21 females. The large intra- and inter-subject variations in the i.v. TYR and NA pressor test results, and the sex difference in the systolic blood pressure response to i.v. TYR, should be considered in assessing the number and gender of subjects required in studies intended to show "significant" differences in the blood pressure response in amine pressor tests.

Adolescent↗
PubMed1988

Practice effect of volunteers in repeated psychometric testing. How to handle this intervening variable in clinical pharmacology studies?

Performance in psychometric tests may show a practice effect with repeated testing. Ideally, a plateau of efficiency should be reached prior to first drug intake. In order to assess the period of familiarization in a multiple choice reaction task (MCRT) 17 healthy subjects practiced the test up to 36 times in the drug free run-in period of 2 trials. A tentative "inclusion criterion" was used in 7 subjects to decide whether their learning phase could be regarded as being finished. Seven to 20 training sessions were required for a first rapid learning phase. There were remarkable differences in the absolute performance of the subjects and in the time course of their practice effect. However, the time course of the learning phase was not dependent on the absolute performance level. By means of the tentative "inclusion criterion" it was possible to reject a subject with a low but highly variable performance. However, it was not stringent enough to indicate the final plateau of efficiency. More "drug free" data concerning the practice effect should be published to enable the users of psychometric tests to make a reasonable selection according to their needs and to help them design their trials properly.

Adult↗
PubMed1987

Influence of oestradiol on alpha 2-adrenoceptor binding sites on intact platelets of young male volunteers.

The specific binding (Bmax) of (3H-methyl)yohimbine to alpha 2-adrenoceptor binding sites on intact platelets was increased by 43% in 6 out of 7 young male volunteers 4 days after a single i.m. injection of 10 mg sustained release oestradiol, and it had returned to the starting value 4 weeks after drug administration. Mean plasma oestradiol was 331 pg/ml on Day 4 and it was within the pre-treatment control range of 19 pg/ml 4 weeks after the injection. A close correlation between the post-injection plasma oestradiol concentration and the increase in alpha 2-adrenoceptor binding sites on intact platelets was not found.

Adult↗
PubMed1987

Pharmacokinetic and pharmacodynamic effects of the novel benzodiazepine antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one in humans.

2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-related and relatively low considering the doses administered. A high plasma concentration ratio of metabolite vs. parent compound (3:1) points to an extensive gastrointestinal first-pass metabolism. CGS 8216 influences the human electroencephalogram similar to anxiolytic and vigilance enhancing drugs in doses which do not change performance of psychometric tests. CGS 8216 antagonizes the diazepam-induced impairment of alertness.

Adult↗
PubMed1987

Intra-subject variability of platelet alpha 2-adrenoceptor binding sites in healthy volunteers.

The specific alpha 2-adrenoceptor binding (Bmax and KD) of (3H-methyl)yohimbine to intact platelets of healthy young volunteers was not significantly different in 7 males and 7 females. Its extent was not dependent on the menstrual cycle. The intraindividual variability was relatively high with means between 6% and 38% for Bmax and between 10% and 39% for KD, respectively. An intra-assay variation of 5.4 to 12.4% for Bmax and of 5.1 to 19.6% for KD contributed to this variability. Therefore, drug effects on platelet alpha 2-adrenoceptor binding in intraindividual cross-over studies are evidential only if the drug-induced changes exceed the intra-subject variability. This should be examined by at least 3 estimates of pre-drug values.

Adult↗
PubMed1986

Central and autonomic nervous system side effects of ketanserin.

A placebo controlled, randomized, double-blind cross-over study was carried out in 7 healthy volunteers in order to study the central and autonomic nervous system side effects of ketanserin in comparison to clonidine. Psychometric performance was assessed as well as electroencephalographic recordings (EEG), saliva production, mean arterial blood pressure (MAP) and pulse rate under placebo conditions (P, 10 ml saline), following 0.15 mg/kg ketanserin or 2 micrograms/kg clonidine i.v. administration. The sedation index as well as the deceleration of EEG frequencies clearly expressed sedation following both, ketanserin and clonidine. Saliva production was significantly decreased by ketanserin (p less than 0.05) and clonidine (p less than 0.01), respectively. MAP was only very slightly reduced by ketanserin, while clonidine caused a small but significant decrease (p less than 0.0001). The pulse rate changes did not reach a clinically important extent. Thus, sedation as main central nervous system side effect and reduction in salivation as autonomic nervous system side effect of ketanserin could be clearly quantified in comparison to placebo and clonidine.

Adult↗
PubMed1985

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effect of intravenous ketanserin on plasma catecholamines and renin activity in normal volunteers.

In a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUCNE) from 13,200 to 18,100 ng X 1(-1) X min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUCE) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng X 1(-1) X min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change.

Adult↗
PubMed1985

Influence of intravenous acetylsalicylic acid and sodium salicylate on human renal function and lithium clearance.

The influence of intravenous acetylsalicylic acid (ASA; D,L-lysine-mono-acetylsalicylate), equimolar doses of sodium salicylate (SA) and placebo (P) on renal function has been studied in 6 healthy female volunteers, in 150 mmol sodium balance, and in lithium (Li) steady state with a plasma Li between 0.6 and 0.8 mmol/l. Following a bolus injection of 0.5 g ASA, 0.444 g SA or P (50 ml saline) given over 10 min and a subsequent continuous infusion of 1.5 g ASA, 1.332 SA or P (150 ml saline) over 170 min, urine was collected for 3 h as well as 6 plasma samples at 30-min intervals. Plasma ASA levels were between 13.8 and 22.1 micrograms/ml and for SA they were 20.8 to 82.6 microgram/ml during ASA infusion, and between 22.5 and 108.9 microgram/ml for SA during SA infusion. Neither ASA nor SA caused a significant change in urine volume, in the renal clearances of Na, K, free water, osmolality, creatinine, inulin and p-aminohippurate (PAH) or in plasma Li level. Renal Li clearance was slightly reduced by SA, from 37.8 to 29.4 ml/min (p less than 0.05). Since renal prostaglandin (PG) synthesis (urinary PGE2 excretion) was 60.6% suppressed by ASA and was not affected by SA, the decrease in Li clearance cannot be related to inhibition of cyclooxygenase in the kidney.

Adult↗
PubMed1984

Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol.

In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the beta-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p = 0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the beta-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.

Adult↗
PubMed1984

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

The 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 (less than 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.

Adult↗
PubMed1983

Mechanism of antihypertensive action of ketanserin in man.

A randomised double blind crossover study was carried out to determine whether ketanserin, a serotonin antagonist with an antihypertensive action in animals, has an alpha 1 adrenergic mediated antihypertensive effect in man. Steady state plasma ketanserin concentrations (mean 88 (SD 19) micrograms/1) and cardiovascular responses measured in five healthy volunteers showed that therapeutic doses of ketanserin significantly antagonised the alpha 1 receptor mediated increase in arterial blood pressure after treatment with methoxamine. Thus the antihypertensive action of ketanserin in man appears to originate from a blockade of peripheral vascular alpha 1 receptors.

Adrenergic alpha-Antagonists↗