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PubMed1980

Effects of CS-386 and diazepam upon the gastric contraction and excitation of lumbar gamma-motoneurons following stimulation of the hypothalamus in the cat.

Effects of a new minor tranquilizer, CS-386 and diazepam were studied upon the gastric contraction and excitation of lumbar gamma-motoneurons following stimulation of some of the brain structures as well as upon the spontaneous gastric motility in the cat. CS-386 inhibited the hypothalamus-induced gastric contraction with little changes in spontaneous motility at doses of 5 and 10 mg/kg (i.d.). Diazepam inhibited both the hypothalamus-induced contraction and spontaneous motility at these doses. The vagal nerve-induced gastric contraction was suppressed by diazepam (5 mg/kg, i.d.) but not by the same dose of CS-386. Bemegride (5 mg/kg, i.v.) antagonized almost completely the depression caused by 5 mg/kg of CS-386, but not that by a dose of 10 mg/kg or 5 as well as 10 mg/kg of diazepam. Excitation of the lumbar gamma-motoneuron following stimulation of the posterior hypothalamus or the mesencephalic reticular formation was depressed by CS-386 or diazepam (10 mg/kg, p.o.), but not by lower doses. Based on the these evidences, it was suggested that CS-386 could be effective in stress-induced gastric lesions with lower side effects in digestive organs than diazepam.

Animals↗
PubMed1983

Anticonvulsant action of diazepam in mice pretreated with caffeine.

Anticonvulsant activities of diazepam in mice given pentylenetetrazol (PTZ), as well as effects of diazepam against potentiating activities of caffeine on these convulsions, were studied. Electroencephalographic (EEG) and electromyographic (EMG) recordings and behavioral observations were employed. First spike, clonic and tonic convulsions induced by PTZ were readily recognized from the EEG recording coupled with EMG recording. Pretreatment of mice with diazepam suppressed the incidence of clonic and tonic convulsions, but did not affect the development of first spike. These anticonvulsive effects of diazepam were also observed when PTZ-induced convulsions were potentiated with caffeine, except for clonic convulsion which was not suppressed with diazepam. The mechanisms of the antagonistic effects between diazepam and caffeine are discussed.

Animals↗
PubMed1989

Potentiation of ifosfamide toxicity by chlordiazepoxide, diazepam and oxazepam.

The effects of chlordiazepoxide, diazepam and oxazepam on the lethal toxicity and metabolic activation of ifosfamide were investigated in mice. Ifosfamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). The prior administration of chlordiazepoxide, diazepam or oxazepam enhanced the toxicity of ifosfamide (778 mg/kg, i.p.) during observation for 6 d after the administration of ifosfamide. In chlordiazepoxide-, diazepam- or oxazepam-treated mice, a higher concentration of active metabolite in the plasma after the administration of ifosfamide (200 or 600 mg/kg, i.p.) was observed as compared with that in mice treated with ifosfamide alone. On the other hand, chlordizepoxide, diazepam or oxazepam markedly enhanced the activity of ifosfamide oxidase in the liver microsomes. These results suggest that the potentiation of ifosfamide toxicity is due to stimulation of the metabolic activation of ifosfamide by chlordizepoxide, diazepam and oxazepam.

Animals↗
PubMed1978

[Behavioral and EEG effects of triazolam in comparison with those of diazepam (author's transl)].

Triazolam was 4 to 5 times as potent as diazepam in reducing hyperemotionality of either septal-lesioned or olfactory bulbectomized rats (O.B. rats), and in suppressing muricide in O.B. rats. This agent was equipotent with diazepam in inhibiting fighting behavior of long-term isolated mice, but was longer in duration of action. Triazolam was approximately 4 times more potent than diazepam in preventing pentetrazol convulsion, but was 10 times less potent in inhibiting maximal electroshock convulsion in mice. The muscle relaxant effect of triazolam as assessed by the inclined screen test was 34 times, and the effect on rotarod performance was 17 times more potent than that of diazepam in mice. Triazolam (0.2 approximately 0.5 mg/kg i.v.) changed the EEG to a drowsy pattern in unanesthetized rabbits with a chronic electrode implant, and suppressed the EEG arousal response to auditory stimulation and electrical stimulation given to either the mesencephalic reticular formation or posterior hypothalamus. The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation were also markedly inhibited by triazolam. These EEG effects of triazolam were qualitatively similar to, but were 4 to 5 times more potent than those of diazepam. These results indicate that triazolam is a potent tranquilizer with a longer duration of action, and the muscle relaxant effect is considerable as compared with diazepam.

Aggression↗
PubMed1985

Inhibitory effect on 3H-diazepam binding and potentiating action on GABA of ethyl loflazepate, a new minor tranquilizer.

A new benzodiazepine compound, ethyl loflazepate (ethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H,1,4- benzodiazepine-3-carboxylate; CM6912) was studied using in vitro experimental systems for its displacement activity on 3H-diazepam binding to the synaptosomal membrane fraction of rat cerebrum and potentiating action on GABA. CM6912 inhibited the specific binding of 3H-diazepam by 25%, 75% and 90% at concentrations of 0.01 microM, 0.1 microM and 1 microM, respectively, while its metabolites CM6913 and CM7116, at 0.1 microM, completely inhibited the binding. Concentrations for 50% inhibition (IC50) were 25 nM for CM6912, 3.2 nM for CM6913 and 1.4 nM for CM7116. These results suggest that the metabolite CM7116 is stronger than its parent compound in displacing the 3H-diazepam binding, and they also suggest that the long-lasting anti-anxietic action of CM6912 might be due to the in vivo formation of CM7116. CM6912, CM7116 and diazepam potentiated the suppressive action of GABA on spontaneous spikes of Purkinje cells in guinea pig cerebellar slices in a dose-dependent manner. Concentrations for 50% suppression (IC50) were 96.0 microM for GABA alone, 75.0 microM for GABA plus diazepam (5 microM), 78.9 microM for GABA plus CM6912 (5 microM) and 60.8 microM for GABA plus CM7116 (5 microM). These findings suggest that CM6912 and CM7116 may potentiate the postsynaptic inhibitory action of GABA in a manner similar to and probably more strongly than diazepam.

Animals↗
PubMed1980

Diazepam-associated thrombophlebitis: a review and discussion of possible prevention.

Intravenous diazepam is an excellent anxiolytic drug for dental patients. Thrombophlebitis associated with its use has prompted this review. Recognition and management of thrombophlebitis are discussed along with the causes of vascular injury after intravenous diazepam. In two histologic studies, Graham and others thought it unlikely that precipitated crystals of diluted diazepam caused postinjection vasculopathology. It seems to be an inherent property of the vehicle or the drug itself. The reviewed methods of minimizing thrombophlebitis after intravenous diazepam are with hepari flush or saline solution flush, steroids, vein size and venipuncture site, the use of a different vehicle, dilutions, and the use of other benzodiazepines. Lorazepam, midazolam, and flunitrazepam are relatively new benzodiazepines that produce less thrombophlebitis than diazepam after injection. These newer benzodiazepines are still being investigated and more clinical trials must be done to recommend any of them as alternatives to intravenous diazepam in dentistry.

Benzodiazepines↗
PubMed1999

Time dependent influence of diazepam on the pharmacokinetics of ibuprofen in man.

Circadian variation in the disease activity of rheumatoid arthritis has been established. Several nonsteroidal anti-inflammatory drugs have been studied for their chronokinetic behaviour. Time dependent influence of diazepam on the pharmacokinetics of diclofenac and naproxen has been reported. We report the time dependent influence of diazepam on the pharmacokinetics of ibuprofen in healthy subjects. Either ibuprofen or ibuprofen with diazepam was administered at 10.00 or 22.00 hours to eight healthy volunteers in a randomized crossover study. Serum ibuprofen levels were estimated by high performance liquid chromatography. There was a significant (p < 0.05) increase in mean elimination half life (2.39 +/- 0.42 to 3.59 +/- 0.35 h) following ibuprofen and diazepam administration compared to ibuprofen alone administered at 22.00 hours. The mean clearance of ibuprofen was therefore lowered from 62.7 +/- 8.9 to 41.7 +/- 2.6 ml/h/kg under the influence of diazepam during the night. Such a time dependent influence of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the dark period.

Adult↗
PubMed2003

Effect of diazepam treatment on metabolic indices in trained and untrained rats.

Exercise training, like diazepam, is commonly employed as a means of reducing anxiety. Both diazepam and exercise training have been shown to modify carbohydrate and lipid metabolism as well as influence calcium metabolism in skeletal muscle. As receptor binding and thereby efficacy of diazepam has been demonstrated to be modulated by the lipid environment of the receptor, and changes in calcium levels can affect a number of intracellular signalling pathways, we sought to determine if the interaction of both chronic diazepam and exercise training would modify selected metabolic indices in an animal model. For this purpose, muscle and liver glycogen, blood glucose and plasma free fatty acids (FFA) were measured in sedentary, exercise trained and exercise trained, acutely exhausted animals. Alterations in lipid and carbohydrate metabolism were observed in all experimental groups. Diazepam treatment alone exerts metabolic consequences, such as elevated muscle glycogen and plasma FFA and depressed blood glucose levels, which are similar to those observed with exercise training. When animals are acutely exercised to exhaustion, however, differences appear, including a reduced rise in plasma FFA, which suggests that long-term diazepam treatment does influence exercise metabolism, possibly as a result of effects on the sympatho-adrenal system.

Animals↗
PubMed1969

Combined action of diazepam and d-amphetamine on fixed-interval performance in cats.

Cats trained under a fixed-interval 5-min schedule of milk presentation were injected with diazepam, amphetamine, and combinations of amphetamine and diazepam. Diazepam increased overall response rate as a function of the dose and disrupted the temporal pattern of responding. Low doses of amphetamine (0.5 mg/kg) usually increased the response rate; higher doses (1 to 2 mg/kg) either decreased the response rate or had little effect. Amphetamine always disrupted the temporal pattern of responding, even though it did not affect the overall rate. When doses of amphetamine that increased the response rate or left it unchanged were combined with diazepam, a potentiated increase in response rate occurred. When doses of amphetamine that decreased the response rate were combined with diazepam, the amphetamine-induced rate decreases were reversed at least partially. Less clear potentiation of disruption of the temporal pattern of responding was observed when amphetamine and diazepam were combined.

Animals↗
PubMed2004

Effects of intravenous midazolam and diazepam on patient response, percentage of oxygen saturation, and hemodynamic factors during periodontal surgery.

BACKGROUND: The purpose of this double-masked study was to evaluate effects of intravenous sedation (IVS) using midazolam or diazepam during periodontal procedures on patient recall, psychomotor response, oxygen saturation, and hemodynamic factors. METHODS: Seventeen patients received either two or three scheduled periodontal surgeries under IVS with midazolam, diazepam, or placebo control. Patients were monitored throughout the procedure for hemodynamic variables, percent oxygen saturation, level of recall of common objects presented at baseline, and psychomotor function via the perceptual speed test (PST). RESULTS: Fifteen patients completed the study with average titrated dosages of 3.3 and 12.1 mg for midazolam and diazepam, respectively. Within the limitations of the study, there were few differences observed between the drugs with regard to hemodynamic variables, oxygen saturation, and overall percentage of objects recalled by patients sedated with either drug. However, midazolam was found to cause a greater incidence of amnesia lasting up to 30 minutes when compared to placebo. Patients on diazepam required an average of 15 minutes longer to recover accuracy as measured by the PST. CONCLUSIONS: The results suggest that diazepam and midazolam each may have advantages for IVS. In procedures lasting over 45 minutes, diazepam appears to be more clinically advantageous including a wider margin of safety during titration and gradual recovery. Midazolam may be used for shorter procedures for faster onset of action, predictable amnesic effects, and relatively rapid recovery.

Adult↗
PubMed2004

Safety of Diastat, a rectal gel formulation of diazepam for acute seizure treatment.

Diazepam rectal gel (Diastat) is the only medication approved by the US FDA for the management of selected, refractory patients with epilepsy, on stable regimens of antiepilepsy drugs, who require intermittent use of diazepam to control bouts of increased seizure activity. An analysis of the safety of diazepam rectal gel reveals that this formulation has certain advantages over intravenous diazepam administration: most notably a very low incidence of respiratory depression, low potential for abuse and the opportunity for out-of-hospital use by non-professional caregivers. Sedation is the most common adverse effect of rectal diazepam treatment, occurring in approximately one-quarter of patients, although drug-induced somnolence is difficult to distinguish from normal post-ictal sedation. Overdosage of diazepam rectal gel is rarely associated with serious clinical consequences, and overdoses of up to 330% of the maximum recommended dosage have been reported without any respiratory or cardiac depression. Under-administration may be a serious safety issue because of morbidity that may result if seizures are not terminated. Chronic administration may cause tachyphylaxis and should be avoided.

Acute Disease↗
PubMed1997

Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers.

A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam. The effect of sertraline on the plasma protein binding of diazepam was also studied. Sertraline 50 mg/day titrated over a 10-day period to 200 mg/day or placebo was administered for 32 days. A single intravenous dose of diazepam 10 mg was given before the start, and after 21 days of sertraline or placebo treatment. The pharmacokinetic analyses were based on data from 20 individuals. The systemic clearance of diazepam decreased by 32% (-0.100 ml/min/kg) in the sertraline group compared with a 19% decrease (-0.054 ml/min/kg) in the placebo group (p = 0.0266). However, this small difference (13%) between the 2 groups was not considered meaningful. Other than a prolonged time to maximum plasma concentration for N-demethyldiazepam, no other pharmacokinetic parameters were significantly altered by sertraline. The plasma protein binding of diazepam was unchanged by concomitant administration of sertraline. These results suggest that sertraline at the maximum recommended dosage under steady-state conditions, and demethylsertraline, the principal metabolite of sertraline, are unlikely to exert significant inhibitory effects on the CYP2C19 and CYP3A3/4 hepatic isoenzymes responsible for the metabolism of diazepam. Therefore, it would be expected that sertraline would, similarly, have a minimal effect on the pharmacokinetic profile of other drugs metabolised by these hepatic isoenzymes.

1-Naphthylamine↗
PubMed1996

Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily.

1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system. 2. Among the P450 forms tested, diazepam was significantly demethylated by CYP2B6, 2C9, 2C19, 3A4 and 3A5, with 2C19 exhibiting the highest rate at concentrations < 0.1 mM, and hydroxylated only by the latter three enzymes, with 3A5 being the most active. The N-demethylation activity of diazepam by 2C19 at a concentration of 20 microM was six times of that by 3A4. However, that by 2C9 was detected at only a trace level. 3. CYP2C19, 3A4 and 3A5 of the ten human P450s catalysed the 3-hydroxylation of nordiazepam, and 2B6, the 2C subfamily and the 3A subfamily catalysed the N-demethylation of temazepam. CYP3A4 exhibited the highest activity of nordiazepam 3-hydroxylation and temazepam N-demethylation. 4. Diazepam N-demethylation by human liver microsomes correlated with diazepam 3-hydroxylation, but not S-mephenytoin 4'-hydroxylation. 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.

Anti-Anxiety Agents↗
PubMed1999

Developmental, neuro and immunotoxic effects of perinatal diazepam treatment in rats.

In utero exposure of rats to low dosages of diazepam (1.0-2.0 mg/kg) has been found to result in depression of the cellular and humoral immune responses during adulthood. Behavioral dysfunctions were also reported in infants from mothers with high benzodiazepine (BDZ) intake during pregnancy. The present experiment was undertaken to reconsider the potential action of diazepam during ontogeny in order to obtain further information about developmental processes using a refined methodology. Time-pregnant rats were treated subcutaneously with diazepam (2.0 mg/kg/day,: group E1) or with diazepam vehicle (group C1) from gestational day 14 to 20. Other dams (group E2) received the same BDZ dose from the 1st to the 21st day of lactation (weaning) or were not treated, remaining undisturbed in their home cages (group C2). The following results were obtained for animals perinatally treated with diazepam compared to groups C1 and C2: 1--increased time for testis descent and decreased time for vaginal opening (group E2); 2--no changes in the dates for ear end eye opening, or incisor tooth eruption (groups E1 and E2); 3--increased locomotor activity in the open-field (group E2) and/or in the plus maze (groups E1 and E2); 4--decreased levels of anxiety measured in the plus maze (groups E1 and E2); 5--decreased macrophage spreading and phagocytosis (groups E1 and E2). These results, which occurred in the absence of overt signs of maternal or fetal toxicity, demonstrate developmental, neuro- and immunotoxic effects of perinatal diazepam treatment in rats.

Animals↗
PubMed1995

Diazepam biphasically modulates [3H]TBOB binding to the convulsant site of the GABAA receptor complex.

Interactions of GABA, bicuculline methochloride and diazepam with [3H]TBOB binding to rat brain membranes were evaluated in vitro. GABA displaced [3H]TBOB binding with and IC50 of 4 microM and a slope factor near unity. The competitive GABA antagonist bicuculline methochloride shifted the displacement curve of GABA parallelly to the right, indicating that the interaction of GABA with [3H]TBOB binding is of an allosteric nature. In the presence of GABA, diazepam displaced the binding of [3H]TBOB according to a two-site model: a high affinity site with an IC50 of about 50 nM and a lower affinity site with an IC50 of about 30 microM. Bicuculline methochloride abolished the nanomolar displacement by diazepam and increased the micromolar IC50 value. These results indicate that the interaction of the high affinity diazepam site with the [3H]TBOB binding site is totally GABA dependent and that the low affinity effect of diazepam on [3H]TBOB binding is at least partially GABA dependent. It is likely that the low affinity potency of diazepam to displace [3H]TBOB binding has physiological relevance.

Animals↗
PubMed1976

Addiction to diazepam.

Literature is reviewed which raises the question of diazepam's addicting potential. To explore this issue, 50 subjects referred from medical, surgical, and psychiatric clinics were evaluated by interview regarding their use of diazepam. Replies to a standardized interview were combined with physicians' ratings of addiction under two conditions: without and then with the knowledge that the drug in question was diazepam. A computer-aided analysis of these data, including a correlation matrix, revealed surprisingly strong evidence for diazepam's capacity to elicit tolerance and withdrawal in this sample. Psychiatric patients were no more "addiction-prone" in this regard than patients given diazepam for medical conditions. Of equal significance, physicians' impressions of addiction were significantly altered toward a more favorable view when they learned that the drug in question was diazepam. Implications for psychiatric and medical practice are discussed, and suggestions for further controlled research offered.

Administration, Oral↗
PubMed1975

Effects of diazepam on the isolated chick embryo heart.

Diazepam decreased the rate and amplitude of contraction in isolated embryonic chick hearts in a dose-dependent manner in both the noninnervated hearts obtained from 4-day-old embryos and the innervated hearts from 7-day-old embryos. The concentration of diazepam necessary to reduce the heart rate and contractile amplitude to 50% of the control values was about 1 X 10(-4) M. Concentrations less than 1.0 X 10(-5) M had no detectable depressant effects. Prior administration of atropine did not alter the depression induced by diazepam. Norepinephrine was able to stimulate the amplitude of contraction in the diazepam-depressed heart while atropine was without effect. The vehicle used in the clinical injectable preparation of diazepam had no depressant effects. The mechanism of action of the diazepam-induced depression on the isolated embryonic chick heart may be a direct depression of the myocardium.

Animals↗
PubMedDate not supplied

A comparative study of clonidine versus a combination of diazepam and atropine for premedication in orthopaedic patients.

Sixty patients in the age group of 18-60 years of A.S.A. Grade I/II risk, scheduled for elective orthopaedic surgeries under general anaesthesia were studied for pre-medication with either oral clonidine or with combination of effects of diazepam & atropine. Patients in Group A (clonidine group) received tablet clonidine 100 mcg (1 tablet) if less than 50 kg in weight and 200 mcg if weighing more than 50 kg two hours before surgery. Patients in Group B (Diazepam-atropine group) received one tablet of Diazepam (10 mg) orally two hours before surgery and injection atropine-sulphate 0.01 mg/kg half an hour preoperatively by intramuscular route. In our study, the sedative and anti-sialogogue effects of clonidine were comparable to those of diazepam-atropine combination, which are commonly used premedicants. The anti-anxiety effect of clonidine was found to be better than that of diazepam-atropine combination. Clonidine also proved to be a better agent for the attenuation of pressor response to laryngoscopy and intubation. Thus, oral clonidine is a better premedicant compared to atropine-diazepam combination. Also, it is a more acceptable agent because of its oral route of administration.

Adjuvants, Anesthesia↗