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PubMed2005

Double-blind study of cyamemazine and diazepam in the alcohol withdrawal syndrome.

OBJECTIVE: Cyamemazine is an original phenothiazine derivative which showed similar efficacy and tolerability to lorazepam during ethanol withdrawal in mice. This study investigated cyamemazine for its efficacy and tolerability in alcohol-dependent patients electing an alcohol withdrawal procedure, in comparison with diazepam. METHOD: A multicenter, randomized, double-blind study in 89 alcohol-dependent patients (CIWA-Ar score between 10 and 30), electing an alcohol withdrawal procedure, was used to find effective doses of cyamemazine and to compare it with diazepam for efficacy and tolerability. On day 1 (D(1)), cyamemazine or diazepam (50 mg and 10 mg capsule, respectively) were administered at hourly intervals to reduce CIWA-Ar = 5, up to a maximum of eight administrations. Starting from D(2), the compounds were given twice a day in progressively decreasing doses during a maximum period of 13 days (D(end)). RESULTS: At h(8) (8 h after the first treatment of D(1)), therapeutic success (CIWA-Ar score </= 5) was achieved in 32 out of 43 ITT patients treated with cyamemazine (74.4%), a value very similar to that of diazepam (32/44; 72.7%). Most such patients (29/32) were controlled with 2-6 capsules of cyamemazine (100-300 mg). In the PP population, cyamemazine (n = 28) was significantly non-inferior to diazepam (n = 33), with a threshold of 10% for non-inferiority bound and 2.5% for one-sided type I error rate. Such therapeutic similarity was confirmed by the analysis of other efficacy criteria. Safety analysis did not show substantial differences between the two treatments. CONCLUSIONS: Cyamemazine showed similar efficacy and tolerability to diazepam for the treatment of alcohol withdrawal symptoms at therapeutic doses in the range 100-300 mg.

Alcohol Withdrawal Delirium↗
PubMed1990

Effect of organic cosolvent-induced skeletal muscle damage on the bioavailability of intramuscular [14C]diazepam.

Organic cosolvents are used in many intramuscular formulations for solubilization of drugs and have been shown to cause skeletal muscle damage (myotoxicity). This study explored the influence of organic cosolvent-induced myotoxicity on the bioavailability of a model compound, diazepam. A tracer (C14) dose of diazepam was selected which did not elicit any systemic pharmacologic effects (viz., hypothermia and sedation) that might alter the pharmacokinetics of the drug. Male New Zealand White rabbits were injected with diazepam dissolved in three cosolvent: water mixtures (20% v/v propylene glycol, 20% v/v polyethylene glycol 400, and 50% v/v polyethylene glycol 400). These mixtures have similar physicochemical properties, but vary 10-fold in their in vitro myotoxicity. Using plasma total radioactivity following intramuscular administration of diazepam, statistical differences were not detected in the area under the curve (AUC), the peak concentration, and the time of the observed peak concentration among these treatments, although the in vivo myotoxicity of these systems (measured by the plasma creatine kinase AUC) varied by 10-fold (p less than 0.01). Limited data on unchanged diazepam levels confirmed these observations. Thus, the degree of skeletal muscle damage caused by these organic cosolvent systems does not seem to affect the bioavailability of a tracer dose of intramuscular diazepam.

Animals↗
PubMed2001

Inhibition of diazepam on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity.

The effects of diazepam on the development of reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine were examined in mice. A single administration of morphine induced hyperactivity and the morphine-induced hyperactivity was inhibited dose-dependently by the administration of diazepam (1, 2 and 4 mg x kg(-1), i.p.), an agonist for benzodiazepine receptor linked to the GABA(A) receptor. Daily repeated administration of morphine developed reverse tolerance to the hyperactivity of morphine. The concomitant administration of diazepam inhibited the morphine-induced hyperactivity and the diazepam administration prior to and during the chronic administration of morphine in mice inhibited the development of reverse tolerance to the hyperactivity of morphine (10 mg x kg(-1), s.c.). Postsynaptic dopamine receptor supersensitivity was also developed in reverse tolerant mice that had received the same morphine. The development of postsynaptic dopamine receptor supersensitivity was evidenced by the enhanced ambulatory activity of apomorphine (2 mg x kg(-1), s.c.). Diazepam also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine may be modulated via the activation of the GABA(A) receptor induced by diazepam.

Animals↗
PubMed1986

Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioural responses to nicotine and diazepam in an elevated X-maze.

Subchronic (6 days) but not acute injections of nicotine (0.4 mg/kg SC) increased spontaneous activity (P less than 0.01) in an elevated X-maze composed of two open and two enclosed runways. Neither acute nor subchronic nicotine altered significantly the ratio of open:enclosed runway entries (O/E ratio). Diazepam (5 mg/kg PO) had no significant effects on spontaneous activity but increased the O/E ratio (P less than 0.05). Acute nicotine increased (P less than 0.01) whereas subchronic nicotine caused a small decrease (P less than 0.05) in the plasma corticosterone concentration. Both acute and subchronic diazepam decreased the levels of the hormone (P less than 0.01 and P less than 0.05, respectively) although the reduction elicited by chronic diazepam was less than that caused by acute diazepam (P less than 0.05). In the experiments with diazepam the plasma corticosterone concentration correlated negatively with the O/E ratio (r = -0.58; P less than 0.05), whereas in the experiments with nicotine plasma corticosterone correlated negatively (r = -0.46; P less than 0.05) with enclosed runway entries. Nicotine injections were associated with a regionally-selective reduction in the 5-hydroxyindole acetic acid (5-HIAA) concentration in the hippocampus (P less than 0.05) and a reduction in hippocampal 5-hydroxytryptamine (5-HT) which approached statistical significance. Chronic, but not acute, diazepam increased (P less than 0.01) hypothalamic 5-HT. The changes in 5-HT and 5-HIAA did not appear to be directly related to the behavioural or adrenocortical responses to either of the drugs.

Animals↗
PubMedDate not supplied

Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment.

Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at non-sedative doses (100 ng/kg-1 micrograms/kg i.p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 receptor. Acute treatment with low doses (0.1-0.75 mg/kg i.p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i.p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i.p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.

Animals↗
PubMed1987

Effect of aging on anticonflict and CNS depressant activity of diazepam in rats.

Male Fischer 344 rats were examined for an age-dependent sensitivity to the anticonflict and central nervous system (CNS) depressant effects of diazepam. A conflict paradigm was used to measure the ability of single intravenous injections of diazepam to attenuate punishment-induced suppression of behavior and to elicit CNS depression in young, mature, and senescent rats. Senescent rats had the lowest behaviorally active threshold dose. However, diazepam at the behaviorally active threshold dose produced a simultaneous increase in punished and unpunished responding in all three age groups. Punished responding was increased more and over a wider dose range in the young and mature rats than in the senescent rats. Sensitivity to the CNS depressant effects of diazepam was over four times greater in the senescent rats than in the other two age groups. In summary, the results indicate that the behavioral effects of diazepam vary with dosage and age of the rat. The male Fischer 344 rat may be a useful animal model for exploring how diazepam elicits age-related behavioral effects in humans.

Aging↗
PubMed1989

Diazepam does not improve the mechanical performance of rat cardiac papillary muscle exposed to chloroquine in vitro.

Diazepam has been reported to decrease the cardiac toxicity of chloroquine but the precise mechanism involved remains unknown. Left ventricular papillary muscles from adult Wistar rats were exposed to 10(-4) M chloroquine and assigned to three groups: group I (n = 10) exposed to chloroquine alone; group II (n = 8) exposed to chloroquine and 10(-5) M diazepam; group III (n = 8) exposed to chloroquine and 10(-4) M diazepam. The main mechanical parameters measured were: maximum unloaded shortening velocity (Vmax), maximum lengthening velocity (maxVr), active force normalized per cross-sectional area (AF/s), contraction-relaxation coupling under low load (R1), load sensitivity of relaxation (Isot.A/Isom.A), and peak power output (Emax) determined from Hill's equation of the force-velocity curve. Data are expressed as mean percent of control values +/- SD, for groups I, II, III respectively. No differences between groups I, II, and III were noted for Vmax (87 +/- 13, 82 +/- 9, 86 +/- 7), maxVr (47 +/- 6, 48 +/- 11, 52 +/- 11), AF/s (87 +/- 16, 91 +/- 10, 83 +/- 11), Isot. A/Isom. A (113 +/- 9, 108 +/- 3, 109 +/- 7), or Emax (75 +/- 10, 81 +/- 12, 72 +/- 16). Chloroquine was shown to be a negative inotropic agent since it decreased Vmax, AF/s and Emax, but diazepam did not restore the intrinsic mechanical performance of rat cardiac papillary muscle exposed to chloroquine, therefore 1) the protective cardiovascular effects of diazepam in chloroquine poisoning are not related to an improvement in intrinsic cardiac mechanical properties; 2) inotropic agents are therefore necessary in combination with diazepam for the treatment of severe chloroquine poisoning.

Animals↗
PubMed1981

Specific oculomotor deficit after diazepam. I. Saccadic eye movements.

Changes in saccadic eye movements before and after up to 10 mg oral diazepam were measured electrooculographically in diazepam-naive humans. Diazepam produced dose-dependent increases in saccade duration and decreases in maximum saccade velocity over a 2--36 degrees range of saccade amplitudes. The magnitude of drug-induced changes in saccade performance was proportional to the size of saccadic movement after 10 mg diazepam. Accuracy of saccade, latency to onset of saccade, latency to time of maximum velocity of saccade, and interval between the end of the initial saccade and the start of any corrective saccade were unaffected by the drug. Diazepam-induced changes in saccades were compared to saccades seen in patients with olivopontocerebellar atrophy reported in the literature, and were contrasted with saccade changes caused by opiates as reported previously. The possible participation of cerebellum in changes in saccadic function after diazepam was discussed.

Adult↗
PubMed1981

Specific oculomotor deficit after diazepam. II. Smooth pursuit eye movements.

Changes in smooth pursuit eye tracking of horizontal sinusoidal target movement before and after up to 10 mg oral diazepam were measured electrooculographically in diazepam-naive humans. Diazepam produced a dose-dependent reduction in gain of pursuit eye movements at target frequencies of 0.4--1.6 Hz. Cross-correlation of eye and track was significantly reduced at most frequencies showing gain reduction after 10 mg diazepam. Eye-target phase relationship was not systematically altered by drug. Visual inspection of smooth pursuit tracking records showed reduced peak-to-peak amplitude of eye tracking along with replacement of smooth pursuit with saccadic pursuit, especially after 10 mg. Changes in smooth pursuit eye tracking after diazepam were similar to those changes reported in the literature associated with olivopontocerebellar atrophy and were quite unlike the changes in smooth pursuit after opiates, as previously reported. The role of cerebellar benzodiazepine binding sites in diazepam disruption of eye tracking was discussed.

Adult↗
PubMed1984

Self-injection of diazepam in naive rats: effects of dose, schedule and blockade of different receptors.

The present series of experiments had two main objectives: The first was to determine the conditions under which self-injection of the benzodiazepine diazepam would be optimal; the second was to identify neurochemical substrates which underlie the maintenance of diazepam self-administration. Data from the first experiment indicated that rats maintained on an FI-1 (Fixed Interval of 1 min) schedule of food delivery self-injected significantly more diazepam than rats not maintained on this schedule. Results from the second experiment demonstrated that the benzodiazepine antagonist Ro 15-1788, and the GABA antagonist bicuculline, significantly reduced diazepam self-administration, but the opiate antagonist naloxone was without effect. Data from the third experiment showed that the dopamine antagonist haloperidol also significantly reduced the rate of diazepam self-injection. Thus, these findings indicate that the acquisition of diazepam self-injection occurs under an FI-1 schedule of food delivery, which has been shown to be middly stressful, while its maintenance depends upon the functional integrity of benzodiazepine and GABA receptors and upon the activity of dopaminergic pathways.

Animals↗
PubMed1980

Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol.

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100 + 50 + 50 + 100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7--1.0 mg/ml and all psychomotor skills were impaired. Diazepam + ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as 'disqualified drivers' more often than after placebo. It is concluded that diazepam, as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery.

Administration, Oral↗
PubMed1985

Is delay of reward mediated by shock-avoidance behavior a critical target for anti-punishment effects of diazepam in rats?

The present study investigated in rats whether variables which may affect the animals' tolerance for delay of reward could be critical for the benzodiazepine-induced release of punished behavior. Rats were subjected to conflict situations during which signalled FR4 non-punished periods (lights-off) alternated with punished periods of different durations signalled by lights-on stimuli. Lever presses during punished periods resulted in the delivery of both one food-pellet and one electric foot-shock (0.45 mA). The antipunishment effect of diazepam (2 mg/kg IP) clearly depended on the duration of the punished periods, release of punished behavior being observed only when punished periods exceeded 1 min. The duration of punished periods required for diazepam-induced release of responding was affected by factors which modified the contrast between rewards received in punished and non-punished periods. One of these factors was the FR schedule imposed during non-punished periods, since the anti-punishment effect of diazepam was observed during short-lasting (30-s and 1-min) punished periods separated by FR24 non-punished periods. A second factor was the ratio of the durations of punished and non-punished periods: diazepam released behavior during 2-min punished periods when the duration of the intercurrent non-punished periods was 1 min, but not when it was 4 min. The predictability of the duration of the punished periods also modulated the effect of diazepam since: with 1 min punished periods, diazepam released punished responding during the first exposures of the rats to the experimental session, but lost part or all its efficacy in animals extensively trained to the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of diazepam on the speed of mental rotation.

The effect of diazepam on spatial visualization was studied using a double-blind crossover design. Diazepam 10 mg (or placebo) was given orally to 12 healthy young men at bedtime, followed again by 10 mg (or placebo) the next morning. One hour after the administration of the morning dose, the subjects performed a mental rotation task. Diazepam effects were analyzed in terms of an information processing model previously constructed to account for performance of the task. Using this method, the slope and intercept parameters of a linear function relating reaction time to task condition (i.e., angular difference in orientation between two identical stimulus figures) were computed for diazepam and placebo conditions. Diazepam significantly increased the slope and intercept of the mental rotation function (P less than 0.05). These results suggest that diazepam impairs spatial visualization ability.

Adult↗
PubMed1986

Reversal of the effect of centrally-administered diazepam on morphine antinociception by specific (Ro 15-1788 and Ro 15-3505) and non-specific (bicuculline and caffeine) benzodiazepine antagonists.

Diazepam, injected into the lateral ventricles reduced the antinociceptive effect of morphine in rats, as measured by the tail-flick method. Specific antagonists of diazepam (Ro 15-1788 and Ro 15-3505) had no effect themselves but prevented inhibition by diazepam of morphine antinociception. Furthermore, the action of diazepam was partially reversed by intracerebroventricular injection of bicuculline or caffeine. These findings support the view that the depressant effect of diazepam on morphine antinociception is specific and GABAergic in nature and that some actions of diazepam are also mediated via the purinergic system.

Animals↗
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↗
PubMed1983

Diazepam antagonizes GABA- and muscimol-induced changes of acetylcholine release in slices of guinea-pig cerebral cortex.

The acetylcholine (ACh) release was studied in superfused, electrically-stimulated slices of guinea-pig cerebral cortex. Muscimol and 4,5,6,7-tetrahydroisoxazolo (5-4-c)-pyridin-3-ol (THIP), as well as exogenous GABA, reduced the electrically-evoked ACh release and enhanced its spontaneous outflow. Picrotoxin antagonized these effects. In addition, picrotoxin and ethanolamine-O-sulphate (EOS) caused opposite changes in transmitter outflow, suggesting the existence of an exogenous GABAergic control on the cholinergic nerve endings. Neither flurazepam 6.6 X 10(-6)--3.3 X10(-5) mol/l nor diazepam 3.3 X 10(-6)--3.3 X 10(-5) mol/l by themselves affected ACh release. Diazepam prevented GABA-, muscimol- and EOS-induced changes in spontaneous and 1 Hz-evoked outflow. Ro 15-1788 3.3 X 10(*-6) mol/l abolished diazepam antagonism vs exogenous GABA. The ineffectiveness of flurazepam and diazepam on normal release (i.e. the lack of potentiation vs the endogenous GABAergic control) supports the view that "synaptic" GABA receptors acting upon the cholinergic nerve endings are not coupled with Benzodiazepine receptors. The unexpected diazepam antagonism vs exogenous GABA and GABA-like compounds can be explained with an unusual Diazepam negative cooperation with "extrasynaptic" GABA receptors, possibly present on the cholinergic terminals. Thus, the rule of benzodiazepine-GABA synergism does not seem always tenable, at least at certain pre-synaptic sites.

Acetylcholine↗
PubMed1993

Sound vibration, a non-invasive stress: antagonism by diazepam.

Rats, subjected to sound-vibration stress, showed an abrupt increase in plasma corticosterone (CS). This stimulation was reliably produced using a Burgess brand "vibro-graver," a standard tool used for engraving. With the tool set at "8" or coarse, the barrel of the tool was placed on the animal's flank and the point held against the side of the metal cage for 15 s. Plasma CS increased to 29.3 +/- 4.7 micrograms/dl at 15 min and 15.7 +/- 1.8 micrograms/dl at 30 min. These levels were significantly higher than animals pretreated with diazepam, 5 mg/kg i.v., 2 h prior to stimulation (9.2 +/- 2.0 and 7.4 +/- 1.5 micrograms/dl, respectively). Animals which were pretreated with CGS-8216 (a mixed agonist/antagonist at the benzodiazepine receptor), 2 mg/kg i.v., 30 min prior to diazepam had the protective effects of diazepam abolished. Sound/vibration produced a significant elevation in plasma CS in animals given CGS-8216 alone; but, this elevation was significantly lower than in vehicle-treated controls. This comparatively lower plasma CS level suggests a partial-agonist, diazepam-like effect by CGS-8216. Experiments were done in conscious unrestrained male Sprague-Dawley rats with chronic i.v. catheters. Except for 15 s stimulation exposure, all animals remained isolated in sound-attenuated one-way vision boxes for the duration of the serial blood sampling. Control stimulation exposure involved similar handling without turning on the engraving tool. These results demonstrate: 1) the usefulness of this tool to provide a repeatable stress stimulus; 2) the ability of diazepam to abolish the stress response; 3) that CGS-8216 can antagonize the action of diazepam; and 4) a demonstration of the partial agonist effects of CGS-8216.

Acoustic Stimulation↗
PubMed1994

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.

Animals↗