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PubMed1978

Plasma concentration of diazepam and N-desmethyldiazepam in children after a single rectal or intramuscular dose of diazepam.

The absorption of diazepam and N-desmethyldiazepam after administration of diazepam solution for parenteral injection per rectum and intramuscularly was studied in 9 children (ages 3--12 years). Rectal administration of diazepam 1 mg/kg led to rapid absorption with plasma levels of 270--320 ng/ml within 5 min, and peak levels of 600--1300 ng/ml 10--60 min after administration. The absorption was comparable to that after intramuscular administration. A second peak in plasma diazepam concentration 6--12 h after dosing was observed in 6 children, which may have been due to mobilization of diazepam from the gastrointestinal mucosa produced by feeding 4 h after administration of the drug. A slowly increasing plasma level of N-desmethyldiazepam was observed during the first 24 h after administration of diazepam.

Child↗

PubMed1976

The cardiovascular effects of diazepam and of diazepam and pancuronium during fentanyl and oxygen anaesthesia.

The cardiovascular effects of diazepam 0.5 and 1.0 mg/kg and diazepam with pancuronium 0.1 mg/kg after fentanyl 0.5 mg/kg were determined in thirteen dogs premedicated with atropine. Fentanyl produced significant reductions in heart rate, cardiac ouptut and arterial blood pressure. Administration of 0.5 mg/kg of diazepam after fentanyl did not significantly alter stroke volume, arterial blood pressure or peripheral vascular resistance but did increase heart rate and cardiac output. Additional diazepam did not further change the heart rate, but did reduce stroke volume, cardiac output, arterial blood pressure and peripheral vascular resistance. Administration of pancuronium after fentanyl and diazepam produced marked elevations in heart rate, cardiac output and arterial blood pressure. There was no difference in mean heart rate and cardiac output when values prior to fentanyl and those obtained three minutes following pancuronium were compared. These data demonstrate that large doses of fentanyl decrease heart rate, cardiac these changes can be partially reversed with diazepam 0.5 mg/kg and completely antagonized with pancuronium 0.1 mg/kg.

Anesthesia, Inhalation↗

PubMed1984

Effect of aminophylline on muscle relaxant action of diazepam and phenobarbitone in genetically spastic rats: further evidence for a purinergic mechanism in the action of diazepam.

The effect of aminophylline on the muscle relaxant action of both diazepam and phenobarbitone was studied in genetically spastic rats of the Han-Wistar strain which exhibit spontaneous tonic activity in the electromyogram of the gastrocnemius-soleus muscle. Both diazepam (0.8 and 4.0 mg/kg i.p.) and phenobarbitone (20 and 30 mg/kg i.p.) reduced the spontaneous activity measured in the electromyogram in a dose-related manner. Aminophylline (50 mg/kg i.p.), a methylxanthine with potent antagonistic activity of adenosine-mediated inhibition, partially reversed the muscle relaxant action of diazepam (4 mg/kg) but not that produced by phenobarbitone. The muscle relaxant effect of phenobarbitone (30 mg/kg) was antagonised by beta-carboline-3-carboxylic acid methylester (beta-CCM), 2 mg/kg i.p. The reversal of the muscle relaxant effect of phenobarbitone produced by beta-CCM was abolished by CGS 8216 (2-phenylpyrazolo-(4,3c)quinolin-3(5H)-one), 5 mg/kg i.p. Aminophylline altered neither the muscle relaxant effect of a low dose of diazepam (0.8 mg/kg) nor the reversal of the muscle relaxant effect of phenobarbitone produced by beta-CCM. These findings indicate that the interaction between diazepam and aminophylline does not involve competition for the benzodiazepine receptor and add further support to the suggestion that purinergic mechanisms may be engaged in the muscle relaxant action of diazepam.

Aminophylline↗

PubMed1998

Subsensitivity to mitochondrial diazepam binding inhibitor receptor agonist FGIN-1-27-induced antiseizure effect in diazepam-withdrawn mice.

We investigated the role of the mitochondrial diazepam binding inhibitor receptor (MDR) in diazepam-withdrawal seizure. In chronically vehicle-treated mice, the potent and selective MDR agonist FGIN-1-27 (N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide: 30 microg/mouse, i.c.v.) markedly increased the threshold for pentylenetetrazole (PTZ)-induced seizure. The antiseizure effect of FGIN-1-27 was blocked by pretreatment with the selective MDR antagonist PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide). In chronically diazepam-treated mice, the seizure threshold of PTZ was decreased during diazepam withdrawal, indicating withdrawal hyperexcitability. Interestingly, FGIN-1-27 (30 microg/mouse, i.c.v.) failed to increase the seizure threshold of PTZ in diazepam-withdrawn mice, in contrast to its effect in chronically vehicle-treated mice. These findings suggest that the sensitivity of MDR-mediated pathways in the brain may be decreased during diazepam withdrawal.

Animals↗

PubMed1978

Plasma concentrations of diazepam and desmethyldiazepam during chronic diazepam therapy.

1 Plasma concentrations of diazepam and its metabolite, desmethyldiazepam, have been measured in both in- and out-patient groups treated with diazepam for periods varying between 1 month and 10 years. 2 The diazepam concentration was directly related to the dose of diazepam ingested and inversely related to the age of the patient. 3 A highly significant relationship was obtained between the concentration of desmethyldiazepam and diazepam. 4 The plasma concentrations of both diazepam and its metabolite were independent of sex, duration fo therapy and patient group.

Adult↗

PubMed1982

RO 15-1788 antagonises the central effects of diazepam in man without altering diazepam bioavailability.

1 In a double-blind, placebo controlled study, the efficacy of Ro 15-1788, a new benzodiazepine antagonist, in blocking the cognitive, psychomotor and subjective effects of diazepam, was investigated in a group of six healthy male volunteers. 2 The central effects of orally administered diazepam (40 mg) were most pronounced 1 h after dosing and persisted for 9 h with decreasing severity. 3 Concurrent oral administration of Ro 15-1788 (200 mg) completely prevented the impairment in cognitive and psychomotor function observed after diazepam alone. 4 The duration of action of Ro 15-1788 was shorter than that of diazepam. 5 Plasma diazepam levels after administration of the diazepam/antagonist combination were very similar to those observed following diazepam alone.

Adult↗

PubMed1983

A prospective randomised controlled trial of diazepam (valium) vs emulsified diazepam (diazemuls) as a premedication for upper gastrointestinal endoscopy.

Two hundred and forty four patients were randomised to receive either diazepam or emulsified diazepam (diazemuls) intravenously prior to routine upper gastrointestinal endoscopy. The groups were comparable with regard to age, sex, medical condition, vein size, and amount of drug administered. A quantitative assessment of symptoms at the injection site during the ensuing week was made by analysing questionnaires on pain and tenderness, which the patients graded each day, on a scale 0-3. Twenty-one out of 82 patients who received diazepam (25.6%) and 22 out of 84 who received diazemuls (26.2%) had local symptoms. Although the mean symptom scores over 7 days for the two groups were not different (5.95 +/- 5.19 and 7.27 +/- 6.30 respectively), more patients who received diazepam reported induration (P = 0.033). In 112 patients, signs of thrombosis in the injected veins were looked for 3-7 weeks later without knowledge of the preparation given. Thrombosis was present in 13 (25%) patients who had received diazepam and two (3.6%) who had received diazemuls (P less than 0.002). Only eight (53%) patients with thrombosed veins had symptoms. Thrombosis after intravenous injection of diazepam or diazemuls may be symptomless, and is significantly less likely following diazemuls.

Adult↗

PubMed1984

Diazepam does not prevent succinylcholine-induced fasciculations and myalgia. A comparative evaluation of the effect of diazepam and d-tubocurarine pretreatments.

To determine the effectiveness of diazepam pretreatment in preventing succinylcholine (SCh)-induced fasciculations and body pains, 587 patients were randomly allocated to six groups. Patients in Group I received no pretreatment and served as controls. Patients in Groups II and III were pretreated with 0.05 mg/kg of diazepam either 4-5 min (Group II) or 8-10 min (Group III) prior to SCh administration. Patients in Groups IV and V received 0.1 mg/kg of diazepam either 4-5 min (Group IV) or 8-10 min (Group V) prior to SCh administration, while patients in Group VI were pretreated with 0.05 mg/kg of d-tubocurarine (dTc) 4-5 min prior to SCh. The succinylcholine dosage was 1.0 mg/kg in Groups I through V and 1.5 mg/kg in Group VI. Fasciculations, intubation conditions and postoperative body pains were evaluated in all groups. Fasciculations were seen in 90% of patients in the control group and 15% in the dTc pretreatment group, while diazepam was ineffective in altering the frequency or intensity of fasciculations. Conditions for intubation were judged to be clinically adequate in all groups. Body pains were seen in 33% of patients in the control group and 28-36% in diazepam-pretreated groups and in only 8% of patients in the dTc pretreatment group. There was no statistically significant difference in the incidence of body pains by virtue of site of operation, age, sex, and inpatient/outpatient status. It is concluded that the problem of postoperative myalgia is significant and that dTc pretreatment is the effective method for prevention of fasciculations and postoperative myalgia. Diazepam pretreatment was ineffective for the prevention of fasciculations and myalgia.

Anesthesia, General↗

PubMed1990

Cytochrome P450IIIA enzymes in rat liver microsomes: involvement in C3-hydroxylation of diazepam and nordazepam but not N-dealkylation of diazepam and temazepam.

Microsomes prepared from livers of male and female rats of nine inbred and outbred strains and of male Sprague-Dawley rats pretreated with monooxygenase-inducing agents were used to study N-dealkylation of diazepam and temazepam and C3-hydroxylation of diazepam and nordazepam. Both C3-hydroxylation reactions were more rapid in male than in female liver preparations, but this gender-dependent pattern was not seen with the N-dealkylation reactions. These results indicate the lack of identity of the monooxygenases responsible for the two kinds of reaction and suggest that male-specific enzyme(s) are responsible for the C3-hydroxylations. Induction studies were undertaken to further define these enzymes. To do this, liver microsomes prepared from male Sprague-Dawley rats pretreated with a variety of agents known to have different monooxygenase induction effects were used. With triacetyloleandomycin, dexamethasone, and phenobarbital pretreatment, the specific activities of the C3-hydroxylation reactions were selectively elevated over corresponding control values. These particular xenobiotics are known to enhance the abundance of cytochrome P450IIIA family enzymes, and our results strongly suggest the involvement of these enzymes in the benzodiazepine B ring monooxygenations. Formation of temazepam was also shown to be inhibited by triacetyloleandomycin. This effect was demonstrated to be equal in both saline-treated and dexamethasone-treated male Sprague-Dawley rat liver microsomes, with the antibiotic present either with diazepam throughout the entire incubation period or initially with NADPH in a preincubation mix for 15 min, following which C3-hydroxylation was initiated by the addition of diazepam. These results confirm the uniformity of the involvement of cytochrome P450IIIA family enzymes in diazepam C3-hydroxylation in untreated and inducer-treated rat liver microsomes. Recent studies with human and rabbit liver microsomal preparations have shown that orthologues of these enzymes also catalyze an equivalent hydroxylation in the B ring of midazolam. These findings, considered with the present results showing that the adjacent methyl N-substituent (absent in nordazepam but present in diazepam) did not affect the selectivity of these enzymes for the C3-hydroxylation reaction, suggest that neither steric nor electronic factors markedly influence catalysis of this monooxygenation by these enzymes.

Animals↗

PubMed1985

A combination of oral diazepam and droperidol for premedication. A double blind comparison with diazepam alone.

Oral diazepam is commonly used as a premedicant. For a given dose there is considerable between patient variation in clinical effect and plasma levels. The addition of droperidol may improve consistency and contribute antiemesis whilst avoiding the undesirable effects of droperidol alone. Ninety patients undergoing minor gynecological or minor urological surgery were given as an oral premedicant either diazepam (0.185 mg/kg) or one of two combinations of diazepam and droperidol (diazepam, 0.185 mg/kg plus droperidol, 0.09 mg/kg; or diazepam, 0.135 mg/kg plus droperidol, 0.09 mg/kg). There was no significant difference between the groups in altering mean anxiety measurements or improving consistency of action as judged by the number of patients having reduced anxiety measurements. Side effects, including nausea and vomiting, were not significantly different between the three groups. In the doses used there was no practical advantage in adding droperidol to diazepam for oral premedication.

Administration, Oral↗

PubMed2002

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra-peritoneal administration of diazepam in mice.

The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.

Animals↗

PubMed1983

Depression of benzodiazepine binding and diazepam potentiation of GABA-mediated inhibition after chronic exposure of spinal cord cultures to diazepam.

Cultures of fetal mouse spinal cord were exposed to 12.6 microM (3.6 micrograms/ml) diazepam for 7 days. After drug removal, benzodiazepine receptor binding was assayed on intact cells and intracellular recordings of diazepam effects on GABA-mediated inhibitory responses were obtained. The biochemical and electrophysiological data revealed significant and parallel reductions in both receptor binding and pharmacological action on GABA responses which did not return to control levels until 3-4 days after removal of diazepam. The results indicate that chronic exposure of spinal cord cultures to diazepam results in a reversible down-regulation of diazepam binding and function.

Animals↗

PubMed1985

Diazepam mixed micelle--comparison with diazepam in propylene glycol and midazolam.

A mixed micelle formulation of diazepam was compared with midazolam and diazepam in propylene glycol for evidence of venous intolerance following IV injection. The overall incidence of venous morbidity was 17% for diazepam mixed micelle, 26% for midazolam and 90% for diazepam in propylene glycol. Diazepam mixed micelle is suggested as a preferable alternative to the standard formulation.

Benzodiazepines↗

PubMed1986

Room temperature phosphorescence of diazepam and its application to the determination of diazepam in serum and in a tablet formulation.

The room temperature phosphorescence (RTP) properties of diazepam were investigated. The filter papers Whatman No. 1, DE-81 and P-81 were tested as substrates and compounds of I(-), Tl(I), Ag(I), Pb(II) and Hg(II) were evaluated as heavy atom enhancers. The RTP of diazepam spotted from neutral (pH approximately 6.2) and acidic (pH approximately 1.6) solutions were compared. The largest RTP signal for diazepam was obtained from Whatman No. 1 in the presence of Hg(II) in an acidic environment. The absolute limits of detection ranged from 0.5 to 1.9 ng depending on the experimental conditions. RTP was evaluated as a simple, rapid and sensitive screening method for toxic levels of diazepam in serum and for the analysis of diazepam in pharmaceutical formulation (tablets).

Journal Article↗

PubMed2000

Diazepam-binding inhibitor/acyl-CoA-binding protein mRNA and peripheral benzodiazepine receptor mRNA in endocrine and immune tissues after prenatal diazepam exposure of male and female rats.

Peripheral benzodiazepine (BDZ) receptor (PBR) and diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP) characterized as a ligand at central BDZ receptors, at PBR with involvement in the regulation of steroidogenesis, and as an intracellular acyl-CoA transporter, are both known to interact with BDZ in adult systems. We investigated their expression after prenatal exposure to BDZ. Diazepam (1.25 mg/kg per day s.c.) was administered to time-pregnant Long Evans rats from gestational day (GD) 14 to 20. Expression of mRNAs encoding for PBR and for DBI/ACBP was studied in the same animals with (33)P-labeled 60 mer oligonucleotides (oligos) by in situ hybridization at GD20, and with (32)P-labeled oligos by Northern blot in steroidogenic and immune organs at postnatal day (PN) 14 and in adult offspring. Prenatal diazepam increased DBI/ACBP mRNA expression in male fetal adrenal and in fetal and PN14 testis. Thymus exhibited increased DBI/ACBP mRNA in male fetuses and in adult female offspring, and reduced organ weight at PN14 in both sexes. In female spleen, an increase in DBI/ACBP mRNA and a decrease in PBR mRNA was seen at PN14. Apart from the finding in spleen, no drug-induced changes in PBR mRNA were observed. The effects of prenatal diazepam were superimposed on treatment-independent sex differences in DBI/ACBP mRNA and PBR mRNA expression. Our data indicate that expression of DBI/ACBP mRNA in steroidogenic and immune organs can be affected by exposure to BDZ during ontogeny, while PBR mRNA expression appears to be less sensitive. They further reveal marked sex differences in the developmental patterns of the two proteins during pre- and postpubertal ontogeny.

Adrenal Glands↗

PubMed1977

Urine catecholamine excretion after large doses of fentanyl, fentanyl and diazepam and fentanyl, diazepam and pancuronium.

The effects of fentanyl (0.5 mg/kg iv), fentanyl with diazepam (1 mg/kg iv) and fentanyl, diazepam and pancuronium (0.1 mg/kg iv) on heart rate (HR), mean arterial blood pressure (BP), cardiac output (QT), urine flow rate and urine epinephrine and norepinephrine excretion were determined in nine dogs. Fentanyl did not significantly change QT or BP but did reduce HR and urine flow rate (P less than 0.05). Urine epinephrine and norepinephrine excretion rates were signicantly increased by fentanyl (P less than 0.05). Diazepam caused no significant further changes in QT, BP or HR 30 minutes after administration, but urine epinephrine and norepinephrine excretion rates were reduced to control (pre-fentanyl) levels. Addition of pancuronium after fentanyl and diazepam increased urine flow rate to pre-fentanyl levels and elevated QT, BP and HR above controls but produced no significant change in urine epinephrine or norepinephrine excretion. These data suggest that fentanyl increases catecholamine blood levels and imply that the latter may be one mechanism by which cardiovascular dynamics are maintained stable during fentanyl anaesthesia. Our findings also demonstrate that cardiovascular stimulation after pancuronium is not associated with increased urinary catecholamine excretion.

Animals↗

PubMed1984

Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure.

Baboons were exposed to diazepam via continuous injection at doses of 0.125-20.0 mg/kg per day intragastrically (i.g.) for 7 days or to 20 mg/kg per day, i.g. for 1 h or 1 to 35 days. After diazepam administration, Ro 15-1788, a benzodiazepine antagonist was given (5.0 mg/kg i.m.) and precipitated benzodiazepine withdrawal was evaluated by scoring individual signs. The severity of the withdrawal, as indicated by the number of the different signs as well as by frequency of individual signs, increased as the dose and duration of diazepam exposure were increased. Consistent elevations in diazepam withdrawal signs were evident after a dose as low as 0.25 mg/kg per day for 7 days and after administration of 20 mg/kg per day for as short as 3-7 days. Data also suggested that history of previous benzodiazepine exposure sensitized animals to subsequent development of physical dependence. Overall, this study suggests that benzodiazepines produce meaningful functional changes in the central nervous system after exposure to relatively low doses and after relatively short durations of exposure.

Animals↗

PubMed1979

Increased specific binding of [3H]diazepam in rat brain following chronic diazepam administration.

Male rats (175 g) were given 30 mg of diazepam in their food daily for 35 days. The animals became drowsy and ataxic from this high dose of drug. After the 35-day dosing, the rats were killed daily, and specific binding of [3H]diazepam and [3H]flunitrazepam was determined in synaptosomal preparations from these and corresponding control rats. On days 3, 4, 6, and 7 after the treatment period the specific binding and specific binding of [3H]diazepam was double that of the control binding and specific binding of [3H]flunitrazepam was 1.67 times that of control. The data indicate that very high doses of diazepam, given for long periods, cause increased specific binding of radiolabeled ligand to brain subfractions. The possible mechanisms and implications are discussed. When lower doses or shorter dosage regimens are used, increased binding is not observed.

Animals↗