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PubMed1990

Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam.

The excretion of diazepam, N-desmethyldiazepam, temazepam and oxazepam in breast milk was studied during withdrawal of a 22-year-old patient from combined high dose diazepam and oxazepam therapy. Concentrations of these benzodiazepines in plasma from both the woman and her nursing infant (1 year old) were also documented. Diazepam, N-desmethyldiazepam, temazepam and oxazepam were found in the maternal plasma and milk with mean milk: plasma ratios of 0.2, 0.13, 0.14 and 0.10 respectively. It was calculated on a mg kg-1 basis that the infant received some 4.7% of the maternal dose. Diazepam could not be detected in the infant's plasma, but low levels of N-desmethyldiazepam (20 and 21 micrograms l-1), temazepam (7 micrograms l-1) and oxazepam (7.5 and 9.6 micrograms l-1) were present. The infant showed no overt physical or mental symptoms of benzodiazepine intoxication.

Adult↗
PubMed1986

A comparative study of diazepam with sustained-release diazepam as oral premedication in minor gynaecological surgery.

Sixty patients undergoing elective minor gynaecological surgery received oral pre-operative medication with 10 mg diazepam in either conventional tablet form on the morning of operation or as the sustained-release tablet the night before. Subjective and objective assessments of the effectiveness of premedication were made. Patients receiving sustained-release diazepam on the night before surgery experienced fewer periods of wakefulness than those who received placebo. Patients who were given diazepam on the morning of surgery felt more drowsy pre-operatively than those who received sustained-release diazepam the night before.

Adolescent↗
PubMed2005

Evaluation of induction by use of a combination of oxymorphone and diazepam or hydromorphone and diazepam and maintenance of anesthesia by use of isoflurane in dogs with experimentally induced hypovolemia.

OBJECTIVE: To compare induction with hydromorphone and diazepam (HydroD) or oxymorphone and diazepam (OxyD) followed by maintenance with isoflurane in dogs with induced hypovolemia. ANIMALS: 6 healthy mixed-breed dogs. PROCEDURE: The study used a crossover design. Measurements were obtained in normovolemic dogs during isoflurane. Hypovolemia was induced (blood loss of 30 mL/kg) and measurements repeated following recovery from anesthesia, after HydroD (hydromorphone, 0.1 mg/kg; diazepam, 0.2 mg/kg; i.v.) or OxyD (oxymorphone, 0.05 mg/kg; diazepam, 0.2 mg/kg; i.v.), after another dose of the same opioid, during administration of isoflurane (end-tidal concentration, 0.9%), and after glycopyrrolate (0.01 mg/kg, i.v.). Significant changes were identified. RESULTS: Induction effect was evident within 1 minute. All dogs were intubated after the second dose of opioid. No significant differences were found between inductions. The HydroD decreased heart rate (mean +/- SEM, -41 +/- 9.8 beats/min), whereas both inductions increased stroke index (0.4 +/- 0.09 mL/kg/beat) and caused moderate respiratory depression. Cardiac index was decreased (-30.2 +/- 6.04 mL/kg/min) and there was minor metabolic acidosis during isoflurane following HydroD, compared with values for anesthetized normovolemic dogs. Glycopyrrolate increased heart rate (50 +/- 8.6 beats/min) and decreased systolic blood pressure (-23.2 +/- 4.87 mm Hg) in dogs induced with HydroD and decreased stroke index (-0.3 +/- 0.08 mL/kg/beat) for both inductions. CONCLUSIONS AND CLINICAL RELEVANCE: Similar effects were detected after administration of HydroD or OxyD in hypovolemic dogs. Either combination should be safe for use in hypovolemic dogs. Administration of glycopyrrolate was not beneficial.

Adjuvants, Anesthesia↗
PubMed1999

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle.

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-D-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals.

Animals↗
PubMed1986

Cardiovascular changes in dogs given diazepam and diazepam-ketamine.

The cardiopulmonary consequences of diazepam (0.5 mg/kg, IV) followed by ketamine (10 mg/kg, IV) were evaluated in 11 dogs. Diazepam did not exhibit a tranquilizing effect and was frequently associated with excessive excitement. It produced minimal cardiopulmonary effects, except for a significant increase in heart rate. Ketamine administration was associated with less cardiovascular stimulation when administered after diazepam than it did when administered alone; the respiratory depression was greater. Compared with ketamine alone, the diazepam-ketamine combination was associated with more vomition, less muscle hypertonus, less seizure activity, and less salivation.

Animals↗
PubMed1985

Liquid-chromatographic assay of diazepam and its major metabolites in serum, and application to pharmacokinetic study of high doses of diazepam in schizophrenics.

In this rapid, sensitive method for simultaneously determining diazepam and its biologically active metabolites--nordiazepam, oxazepam, and temazepam--in serum, 250 to 1000 microL of serum is extracted with ether and the extracted compounds are quantified by "high-performance" liquid chromatography on a Shimpack FLC-C8 microparticulate column. Absorbance of the effluent is monitored at 254 nm. The limit of detection in serum is about 10 micrograms/L for each drug. Analytical recovery of each drug added to the serum varied from 91 to 102% for oxazepam and temazepam, from 82 to 99% for nordiazepam and diazepam. Within-day and between-day CVs ranged from 2 to 5% for oxazepam and temazepam, and from 2 to 7% for nordiazepam and diazepam. We also report results on using this assay in a pharmacokinetic study of high doses of diazepam used to treat chronic schizophrenic patients.

Administration, Oral↗
PubMed1980

Hemodynamic effects of diazepam and diazepam-nitrous oxide in patients with coronary artery disease.

Circulatory responses following intravenous diazepam (0.5 mg/kg) and the subsequent addition of 50% nitrous oxide were studied in 14 patients undergoing elective aortocoronary saphenous vein bypass operations. No patient was receiving propranolol. Preanesthetic medication was with morphine and scopolamine. Diazepam was continuously infused over a 10-minute period. At the conclusion of the infusion, systolic and mean arterial pressures were 13% lower than control awake values (p less than 0.05). Heart rate, cardiac output, right atrial pressure, pulmonary arterial pressure, pulmonary artery occluded pressure, and systemic and pulmonary vascular resistance were not changed. The subsequent addition of nitrous oxide resulted in no further statistically significant changes except for a 2.4 torr increase in right atrial pressure (p less than 0.05). In contrast, previous data collected from similar patients demonstrated significant reductions in blood pressure and cardiac output while systemic and pulmonary vascular resistance and pulmonary artery occluded pressure were increased when nitrous oxide was added following the administration of morphine (1 to 2 mg/kg). It is concluded that the observed minimal circulatory changes following diazepam administration and the subsequent addition of nitrous oxide make diazepam-nitrous oxide a valuable alternative to a morphine-nitrous oxide induction of anesthesia in patients with coronary artery disease.

Coronary Disease↗
PubMed1990

[Effects of diazepam and N(6)-cyclohexyladenosine on the level of diazepam-binding inhibitor in structures of the hippocampus during immobilization stress].

The Diazepam-binding inhibitor (DBI) levels were studied under stress-reaction condition and after diazepam and N6-cyclohexyladenosine injections. The radioimmune method was used to study the DBI levels. It was shown, that DBI level increased during stress-reaction. Diazepam and N6-cyclohexyladenosine injection decreased DBI level in these conditions. On the basis of these data the authors proposed the hypothetic model of interaction between adenosine receptors and GABA-Benzodiazepine-receptor complex.

Adenosine↗
PubMed1990

Diazepam and Ro 15-1788 increase absence epilepsy in WAG/Rij rats chronically exposed to diazepam.

The mechanisms underlying tolerance to benzodiazepines were investigated by injecting diazepam (5 mg/kg) twice daily for 23 days in WAG/Rij rats (an animal model for non-convulsive absence epilepsy). After this the rats received either the agonist, diazepam, or the antagonist, flumazenil (Ro 15-1788). EEG analyses showed that both compounds increased the amount of absence epilepsy-like phenomena. This suggests that repeated administration of diazepam moves the benzodiazepine receptor spectrum towards the inverse agonist end.

Animals↗
PubMed1991

Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons.

Acute i.m. injections of benzodiazepine receptor ligands were administered to baboons before 1-h observational sessions. The agonist midazolam produced sedative effects, the antagonist flumazenil produced no behavioral effects, the inverse agonist FG7142 produced tremor and the inverse agonist 3-carboethoxy-beta-carboline hydrochloride (beta CCE) produced tremor, vomiting, jerks and seizures. Co-administration of these drugs (midazolam + beta CCE, midazolam + flumazenil or flumazenil + beta CCE) produced a mutual antagonism of these effects. Compared to the non-dependent condition, in the diazepam-dependent condition (baboons maintained on 20 mg/kg per day diazepam) and withdrawn condition (dependent baboons tested during withdrawal), midazolam produced decreased sedative effects, flumazenil produced increased effects (i.e., tremor, vomiting and jerks), and beta CCE produced increased frequency of seizures. Taken together, these data suggest that (1) benzodiazepine receptor ligands lie on a continuum of behavioral activity, and (2) chronic diazepam administration alters the behavioral effects of these benzodiazepine ligands, producing a shift in the direction of the inverse agonist.

Animals↗
PubMed1985

Effects of the rectal administration of diazepam. Diazepam concentrations in children undergoing general anaesthesia.

Diazepam 1 mg/kg body weight was administered rectally to 14 children (11-22.5 kg) before minor surgery under general anaesthesia. Administration in solution (n = 7) resulted in a rapid increase in serum concentrations which were maintained for 8 h. Administration by suppository (n = 7) resulted in significantly lower serum concentrations at 10 and 20 min, but higher concentrations at 2 h. At other intervals the concentrations did not differ from those reached after administration of diazepam in rectal solution. These results favour for use of a solution when rectal diazepam is used for premedication in children.

Anesthesia, General↗
PubMed1980

Effects of diazepam on adenosine and acetylcholine release from rat cerebral cortex: further evidence for a purinergic mechanism in action of diazepam.

1 Diazepam administered intraperitoneally (0.25 mg/kg) enhanced the rate of efflux of [3H]-adenosine and its metabolites from rat cerebral cortex. At a lower dose (0.05 mg/kg), this effect could be detected in only one of four rats. 2 Diazepam (0.05 and 0.25 mg/kg i.p.) depressed acetylcholine release from the rat cerebral cortex. Its effect was reversed by theophylline. 3 Theophylline (15 and 30 mg/kg) enhanced acetylcholine release from the rat cerebral cortex. Diazepam (0.25 mg/kg) administered after theophylline failed to cause a reduction in the rate of release, rather there appeared to be a further enhancement of release. 4 Pentobarbitone sodium (5, 10 and 15 mg/kg i.p.) did not elicit any increase in adenosine release. 5 These results support the proposal that benzodiazepines may exert their pharmacological actions by preventing adenosine uptake, thus enhancing the levels of extracellular adenosine.

Acetylcholine↗
PubMed1979

Use of the overturn end point in goldfish to measure the interaction of diazepam and ethanol and the effects of the binding of diazepam to bovine serum albumin.

Over the ranges 2.8 X 10(-5) to 8.78 X 10(-5) M diazepam and 4.85 X 10(-2) to 1.22 X 10(-1) M ethanol, addition of the effects of these agents on the overturn end point in goldfish was observed. The addition of bovine serum albumin (1.56 X 10(-5) M) to aqueous solutions of diazepam modifies the diazepam effect by reducing the "free" drug concentrations.

Animals↗
PubMed1983

Recurrence of intravenous-diazepam-induced phlebitis from oral diazepam.

A patient who developed phlebitis from the intravenous administration of diazepam is described. This episode resolved in two days after treatment with moist heat packs. Three days after complete resolution, the phlebitis recurred approximately eight hours after a single oral dose of diazepam. This recurrence of phlebitis resolved slowly over seven days, with warm soaking and aspirin therapy. Oral diazepam may have exacerbated the initial phlebitis by interfering with a subclinical healing process.

Administration, Oral↗
PubMed2002

Establishment of a diazepam preference in human volunteers following a differential-conditioning history of placebo versus diazepam choice.

This study examined whether preference for a drug (diazepam or placebo) could be switched using conditioning procedures. During the first 4 sessions of Phase 1, 6 participants received 5 mg of diazepam or placebo under double-blind conditions. During the remaining 5 sessions of Phase 1, participants selected the drug they wished to receive. The first 4 sessions of Phase 2 were a replication of Phase 1, except that following ingestion of the drug, participants completed a computer task for which they could earn money. Payment for the computer task was lowest following ingestion of the drug they preferred in Phase I and highest following the drug they had avoided. Preference was reassessed during the last 5 sessions of Phase 2. Five of the participants preferred placebo in Phase 1 but diazepam in Phase 2. Subjective responses to the drugs also changed across the 2 phases.

Adult↗
PubMed1983

Influence of diazepam and methylphenidate on identification of rapidly presented letter strings: diazepam enhances visual masking.

The effect of diazepam (0, 5, 10 mg) and methylphenidate (0, 5, 10 mg) on the identification of briefly displayed letter strings composing words was investigated. Each letter was presented for 70 ms. The interstimulus interval (ISI) between two successive letters was 10, 100 or 200 ms. The length of the words (WL) was three, five, seven or nine letters. The dependent variable was the number of correctly identified words. As predicted, strong visual masking effects, the strength of which was dependent on ISI and WL, appeared. In the 10 ms condition, diazepam at both doses, but not methylphenidate, further enhanced masking. It is suggested that the results reflect the effect of GABA on masking, and support certain psychological theories about the inhibitory neuronal pathways that are involved in masking. The human peripheral visual system is a promising model for the experimental assessment and integration of pharmacodynamic, neurophysiological and psychological observations.

Adult↗
PubMed1989

Therapeutic and hypothermic properties of diazepam altered by a diazepam-chlorpromazine association.

Rats were injected (IP) with diazepam (2.5 mg/kg) and chlorpromazine (10.0 mg/kg) with a 30-min interval between the two injections. After 10-12 repeated drug pairings of this type, the thermic, muscle relaxant, and anxiolytic responses of the animals to diazepam alone were tested. These tests revealed: 1) an enhanced hypothermia (rectal temperature), 2) an attenuated muscle relaxant effect (inclined plane test), and 3) a potentiated anxiolytic effect (plus-maze test). Although various interdrug associations have previously been demonstrated using other measures of conditioning, this is the first instance in which changes in the therapeutic effects of a drug (in this case, muscle relaxation and anxiety reduction) have been obtained with this procedure.

Animals↗
PubMed1993

Synthesis and structure-activity relationships of 3,5-disubstituted 4,5-dihydro-6H-imidazo[1,5-a][1,4]benzodiazepin-6-ones at diazepam-sensitive and diazepam-insensitive benzodiazepine receptors.

A series of imidazobenzodiazepin-6-ones possessing varying substituents at the 3- and 5-positions were synthesized and evaluated for their affinities at diazepam-sensitive (DS) and diazepam-insensitive (DI) benzodiazepine receptors (BzR) in rat cortical and cerebellar membranes. Replacement of an ester substituent at the 3-position with a carbamate, acetylamino, formylamino, isothiocyanato, 2-oxazolinyl, 2-benzoxazolyl, or p-tolylsulfonyl groups lead to > 100-fold reductions in affinity at both DS and DI BzR. Replacement of a methyl group on the nitrogen at the 5-position with propyl, allyl, or phenethyl groups also led to significant reductions in affinity at both BzR isoforms. However, incorporation of a benzyl group yields ligands (11f,h,i and 14a-c) with moderate to high affinities at DS BzR, suggesting the presence of a hydrophobic pocket at the receptor site. Introduction of chlorine at the 7-position enhances ligand affinity at DS BzR while chlorine at the 8-position decreases affinity (IC50: 11f, 9.3 nM; 11h, 2.4 nM; 11i, 37.8 nM). In contrast, chlorine substitution at the 7- as well as the 8-position increases affinity at DI BzR (Ki: 11f, 112 nM; 11h, 20.2 nM; 11i, 10.9 nM). Compound 11 is among the few described high affinity DI-site ligands with a selectivity comparable to that of Ro 15-4513. Despite their in vitro affinities, compounds 11f, 11h, and 11i exhibit low in vivo activities that may be attributable to unfavorable metabolic or pharmacokinetic properties.

Animals↗