Noradrenergic regulation of GABAergic inhibition of main olfactory bulb mitral cells varies as a function of concentration and receptor subtype.

The main olfactory bulb (MOB) receives a rich noradrenergic innervation from the pontine nucleus locus coeruleus (LC). Previous studies indicate that norepinephrine (NE) modulates the strength of GABAergic inhibition in MOB. However, the nature of this modulation and the NE receptors involved remain controversial. The goal of this study was to investigate the role of NE receptor subtypes in modulating the GABAergic inhibition of mitral cells using patch-clamp electrophysiology in rat MOB slices. NE concentration dependently and bi-directionally modulated GABA(A) receptor-mediated spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) recorded in mitral cells. Low doses of NE suppressed sIPSCs and mIPSCs because of activation of alpha2 receptors. Intermediate concentrations of NE increased sIPSCs and mIPSCs primarily because of activation of alpha1 receptors. In contrast, activation of beta receptors increased sIPSCs but not mIPSCs. These results indicate that NE release regulates the strength of GABAergic inhibition of mitral cells depending on the NE receptor subtype activated. Functionally, the differing affinity of noradrenergic receptor subtypes seems to allow for dynamic modulation of GABAergic inhibition in MOB as function of the extracellular NE concentration, which in turn, is regulated by behavioral state.

Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations.

The interaction between a single dose of 20 mg of prazepam and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by nine objective performance tests, eight visual analogue self-rating scales and measurement of prazepam and ethanol plasma concentrations, using a double-blind three-way crossover design. The volunteers were each given three treatments (prazepam+ethanol, placebo+ethanol and prazepam alone), separated by a 2-week interval. They completed the performance tests before treatment and 1.5 and 4 h thereafter, and the self-rating scales before treatment, 1.5, 4 and 8 thereafter. To determine prazepam and ethanol plasma levels, venous blood samples were drawn before drug intake and 0.25, 0.5, 1, 1.5, 3, 4, 5 and 8 h thereafter. In two of the performance tests: auditory reaction time and digit symbol substitution, the combination of prazepam and ethanol was shown to impair performance more than either drug taken alone 1.5 h after their administration. A similar result was found for the drowsiness scored in the self-ratings. The time needed to complete the two-symbol cancellation test was longer when the subjects received prazepam either alone or combined with ethanol. Simultaneous ingestion of prazepam and ethanol did not alter the bioavailability of either drug.

Comparison of the effect of two prazepam formulations on psychomotor and cognitive function in healthy volunteers.

A double-blind crossover design was used to evaluate the effect of two different formulations of prazepam, on motor and cognitive functions and subjective symptoms. Ten healthy male volunteers received 20 mg of prazepam both in tablet and liquid (as drops) formulation, separated by a 1 week interval. All subjects completed a battery of 9 performance tests 2.25 h and 4.75 h after drug intake (corresponding to the times of peak plasma concentration). They also rated themselves on eight visual analogue scales before, 2 h, 4.5 h and 8 h following drug intake. A significant difference between liquid drops and tablets was demonstrated in 4 of the 9 performance tests and 2 of the 8 items of the self rating scales. These results suggest that a single dose of prazepam administered in liquid drop form exhibits greater sedative properties than the same dose administered as tablets in healthy volunteers, probably as a result of more rapid absorption.

Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo.

Thirty-nine healthy volunteers received single oral doses of either alprazolam (1 mg), lorazepam (2 mg), prazepam (20 mg), or placebo in a randomized, double-blind, parallel group study. Plasma drug concentrations, subjective self-ratings, and the digit symbol substitution test (DSST) were evaluated during 24 hours after dosage. Alprazolam was absorbed rapidly and produced correspondingly rapid sedation and impaired DSST performance. These effects also resolved rapidly, being similar to placebo by 4 to 6 hours after dosage. Sedative and DSST-impairing effects of lorazepam were of slower onset but longer duration than those of alprazolam. After oral prazepam, appearance of desmethyldiazepam in plasma was slow, with minimal sedative and DSST-impairing effects. Twenty-four hours after dosage, both alprazolam and lorazepam significantly impaired recall of a list of 16 words learned previously 3 hours after dosage. Thus benzodiazepines with approximately equivalent clinical anxiolytic properties may have different sedative, performance-impairing, and amnesic profiles after single doses in healthy volunteers; these differences are explained at least in part by pharmacokinetic variations.

Plasma concentrations and clinical effects after single oral doses of prazepam, clorazepate, and diazepam.

In a double-blind parallel-group pharmacokinetic and pharmacodynamic study, 31 healthy volunteers received single oral doses of prazepam (10 mg), clorazepate (7.5 mg), or diazepam (5 mg). Appearance in plasma of diazepam and of desmethyldiazepam was rapid after administration of diazepam and clorazepate, respectively, with peak plasma concentrations reached within an average of 1 hour. After oral prazepam, however, desmethyldiazepam appeared in blood slowly, with the highest mean concentration at 6 hours postdosage. Clinical self-ratings of fatigue and of "feeling spacey" were significantly different among groups, with changes over baseline being more marked with clorazepate and diazepam than with prazepam. Thus, differences in absorption rate of orally administered benzodiazepines can lead to differences in the intensity of single-dose effects, despite administration of doses that are equivalent in terms of long-term anxiolytic efficacy.

[Effect of prazepam on experimental hypertensive models].

Combined effects of prazepam and trichlormethiazide (TCM) which were given simultaneously were studied in renal hypertensive rats (1-kidney type) and DOCA hypertensive rats. In this study the blood pressure was measured by the plethysmographic method. Orally administered prazepam alone did not show any appreciable effect on the blood pressure, while TCM, even when administered alone, exhibited marked and long-lasting hypotensive effects of both hypertensive rats. In addition, the hypotensive effect of TCM was apparently potentiated by the concurrent use of prazepam. In the experiment where conscious and unconstricted spontaneous hypertensive rats (SHR) were used, the pressor response and tachycardia were observed when foot shock (acute stress) was loaded. This pressor response was the "all or none" type and a threshold existed. In contrast to the pressor response, the degree of tachycardia varied depending on the intensity of the stress. The similar responses were also observed in normotensive rats, although the degrees of the responses were significantly weaker than those in SHR. Prazepam given alone obviously suppressed the cardiovascular responses mentioned above. The present results suggest that prazepam is an useful drug for the treatment of hypertension.

The influence of tilidine and prazepam on withdrawal reflex, skin resistance reaction and pain rating in man.

Pain rating, withdrawal reflex and skin resistance reaction upon electrical skin stimuli were studied on 15 male volunteers under placebo, tilidine and prazepam. Tilidine (Valoron) is an orally applicable narcotic analgesic, with a mode of pain relief presumably similar to morphine; the tranquilizer prazepam (Demetrin) belongs to the benzodiazepine group. Significant reduction in all measured reaction amplitudes was found under tilidine, whereas prazepam reduced significantly only the skin resistance reaction. The relative drug-induced changes in reaction amplitudes, related to the corresponding placebo value, were independent of stimulus intensity for all investigated reactions. Therefore, fitted power functions re = a . Sn between reaction amplitudes re and stimulus intensity S showed a decrease in parameter a under the investigated drugs, whereas the exponent n remained constant. High correlations between parameters a and corresponding reciprocal threshold currents could be shown for all reactions measured. Furthermore the drug-induced changes of withdrawal reflex amplitude and of subjective estimation were found to be correlated over subjects. In contrast, no correlations were found between variations in skin resistance reaction and magnitude estimation due to the selected drugs, i.e., the influence of the drugs on the sensory component of pain sensation and on the skin resistance reaction were independent effects.

[Pharmacokinetics of oral prazepam]. / Zur Pharmokokinetik nach oraler Gabe von Prazepam.

The biotransformation pathways following oral administration of prazepam are characterized. The time course of the active metabolite descyclopropylmethylprazepam (= norprazepam), representing 80-90% of all prazepam metabolites in plasma, can be described by an open one compartment model with a mean elimination half life of 70 h and a plasma clearance of 1.0-1.4 l/h. 3-5 h after single doses of 20 mg prazepam, the corresponding peak levels of norprazepam are 120-160 ng/ml. There is only a slight uptake of norprazepam into red blood cells and a relative low secretion into breast milk. Following repeated doses of daily 20 mg prazepam steady state levels of norprazepam are 600-800 ng/ml. The slow build-up of the active metabolite and the long elimination half life ensure continuous plasma levels with small fluctuations.

Influence of anxiolytic drugs (Prazepam and Diazepam) on respiratory center output and CO2 chemosensitivity in patients with lung diseases.

Occlusion pressure at 0.1 s (P0.1) and its evolution during progressive hyperoxic hypercapnia (CO2 chemosensitivity) were measured in 40 patients. Most of them (26) were affected by asthma and /or chronic bronchitis and had mild obstruction and hypoxemia. Measurements were made after 2 days of oral prazepam, diazepam or a placebo (single-blind study). Diazepam induced a significant decrease in P0.1 without affecting CO2 chemosensitivity. In contrast, prazepam did not significantly modify P0.1 or CO2 chemosensitivity. However, P0.1 decreased in 5/18 individual cases. 1 week of treatment by prazepam has advantages over diazepam by not depressing respiratory center output.

Classification and assessment of cerebral bioavailability of lopirazepam (D-12524) by quantitative EEG and psychometric analysis.

In this double-blind, placebo-controlled study the CNS efficacy and pharmacodynamic properties of 3-hydroxy-5-(o-chlorophenyl)-7-chloro-1,2-dihydro-3H-pyrido[3,2-e]-1,4-diazepin-2-one (lopirazepam, D-12524) was investigated in a group of 10 normal volunteers. Quantitative EEG and psychometric analyses and clinical evaluations were done before as well as 2, 4, 6 and 8 h after oral administration of single doses of placebo, 3 mg, 5 mg and 10 mg lopirazepam and 10 mg prazepam. EEG digital computer period analysis demonstrated dose-dependent changes which are typical of the class of anxiolytics and which started in the 2nd hour, peaked in the 4th hour and lasted after 3 mg, 5 mg and 10 mg up to the 4th, 6th and 8th hour, respectively, 10 mg D-12524 produced an additional augmentation of slow waves indicating sleep-inducing qualities in this dosage. The equipotent dosage to 10 mg prazepam seems to be 5 mg. Psychometric analyses demonstrated an improvement in attention, psychomotor performance, mood and affectivity after 3 mg, opposite changes after 10 mg D-12524. Flickerlight fusion, reaction time, after-image and EAS score were determined as well. Data concerning side effects, pulse rate and blood pressure suggested a good tolerance of the drug.

Effect of benzodiazepines on age of vaginal perforation and first estrus in mice.

Female mice which received chlordiazepoxide, diazepam, oxazepam, prazepam, flurazepam, or nitrazepam prenatally and postnatally had delays in the age of vaginal perforation and first estrus concomitant with reduced postnatal growth. Females exposed prenatally showed no growth deficits, but in four treatments had delayed vaginal opening. However, the age of first estrus was generally less than the control.

The effect of minor tranquilizers on psychomotor performance.

The effect of a standard daily regimen of chlordiazepoxide, prazepam (a new benzodiazepine tranquilizer), and placebo were examined in a three way double-blind comparison for a sample of normal volunteers. The criteria include a limited spectrum of psychomotor functions. A learning effect was conspicuous for all drugs on all criteria during the day-long sequence of ten trials. For the most part the differences between the drug groups were insignificant, but there were distinctive modifications in the performance of the chlordiazepoxide group. The clearest effect of the tranquilizer medications was found in the time estimation tests. Paradoxically, the drugs correct a naturally occurring perceptual error.