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At least 19 recordsLinked to original sources
PubMed1990

On the use of diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide), as adjunct antidotes in the treatment of organophosphorus intoxication in the guinea-pig.

Diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide) have been used as adjunct antidotes to pyridostigmine and atropine against the organophosphate, soman, in the guinea-pig. Both added significant protection to the pyridostigmine/atropine treatment. Animals pretreated with diazepam, 60 min before soman, were "better" protected than animals given an equimolar dose of pro-diazepam therapeutically 1 min after soman. A pretreatment with diazepam for three days further increased the protection. A therapeutic dose of pro-diazepam, 1 min after soman, gave no further protection, to the three day diazepam pretreatment. The serum concentrations of diazepam (given i.p.) and desmethyldiazepam (given i.m.) were determined by GLC after diazepam (i.p.) and pro-diazepam (i.m.) were given. The protection, relative to the control, provided by the diazepam pretreatment (60 min before and for three days before soman) correlated linearly, r = 0.9898, with the serum values of diazepam achieved at these times. Our data suggest that diazepam as adjunct to pyridostigmine and atropine administered as pretreatment gives a "safer" protection, than an equimolar dose of pro-diazepam given therapeutically.

Animals↗
PubMed2003

Flumazenil attenuates development of tolerance to diazepam after chronic treatment of mice with either isoflurane or diazepam.

UNLABELLED: In an effort to clarify the mechanism of action of isoflurane, we studied the effect of flumazenil on mice chronically treated with isoflurane or diazepam. Mice were pretreated with diazepam, isoflurane, or saline, with and without flumazenil. After 2 wk, responses to isoflurane and diazepam were assessed, and central benzodiazepine receptor (CBR) binding characteristics were assayed. Mice pretreated with isoflurane failed the horizontal wire test at a larger isoflurane concentration (0.5%) compared with saline-pretreated mice (0.4%) (P < 0.05). These differences did not occur when flumazenil was added to the pretreatment. After the administration of diazepam, 20% of diazepam- and 11% of isoflurane-pretreated mice failed the horizontal wire test, versus 50% and 44% when flumazenil was added to either drug (P < 0.002) and 80% and 100% in the saline and saline plus flumazenil-treated mice. The increased CBR density due to flumazenil was attenuated by the coadministration of isoflurane or diazepam. Flumazenil attenuated the development of tolerance to diazepam after chronic treatment with diazepam or isoflurane and attenuated the development of tolerance to isoflurane. Isoflurane, like diazepam, attenuated the effect of flumazenil on CBR ligand binding. These findings suggest that isoflurane shares a mechanism of action with diazepam, probably via the gamma-aminobutyric acid system, most probably the CBR. IMPLICATIONS: Flumazenil attenuates the development of tolerance to isoflurane and diazepam after chronic isoflurane pretreatment. Isoflurane, like diazepam, attenuates the increase in central benzodiazepine receptor (CBR) density caused by flumazenil. These findings suggest that isoflurane and diazepam share a mechanism of action, most probably via the gamma-aminobutyric acid system and the CBR.

Anesthetics, Inhalation↗
PubMed1975

Plasma concentrations of diazepam and its metabolites after peroral, intramuscular, and rectal administration. Correlation between plasma concentration and sedatory effect of diazepam.

Plasma levels of diazepam, N-demethyldiazepam and free oxazepam were measured gaschromatographically in ten healthy volunteers after 5 mg of diazepam perorally, intramuscularly and rectally (with three different kinds of suppositories). The best absorption of diazepam was found after peroral administration. After an intramuscular injection a delayed absorption with low plasma concentrations of diazepam was found. The basal component of a diazepam suppository seems to have a great effect on the rectal absorption of diazepam. Two of the three different kinds of diazepam suppositories caused higher plasma diazepam concentrations than the intramuscular injection of the drug. There were no great differences in the amount of the metabolites of diazepam after different kinds of administration. The subjective sedatory effect of diazepam lasted approximately as long as the fast distribution of diazepam from plasma took place. A very highly significant correlation between plasma concentration and subjective sedatory effect of diazepam after a single dose was found.

Administration, Oral↗
PubMed1986

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150% and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.

Adult↗
PubMed1994

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations.

It has proven difficult to demonstrate and study the "anxiogenic" quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent "distress" responses during diazepam withdrawal. Three experiments evaluated the association between USV and "distress" by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20-30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1-3 mg/kg) and gepirone (0.1-1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the "anxiogenic" effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP x 5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1-1 mg/kg IP), but not diazepam (3-20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5-10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1976

Feto-maternal concentrations of diazepam and W-demethyldiazepam after intra-amniotic diazepam injection.

Ten milligrams of diazepam were injected intraamniotically in 8 mothers prior to therapeutic abortion between 12 and 19 weeks. The diazepam concentrations in the maternal plasma were comparable to those found after the same intramuscular diazepam dose to the mother. The concentration of diazepam in the amniotic fluid 12 to 18 hours after the injection was no longer significantly higher than in the maternal plasma. The concentrations of diazepam in the fetal plasma, liver and brain were comparable to the concentrations resulting from a 10 mg intramuscular diazepam dose to the mother about 2 hours before legal abortion. The feto-maternal ratio of diazepam was of same magnitude as after the intramuscular application to the mother. The results indicate that the disappearance of diazepam from the amniotic fluid in this stage of pregnancy occurs extraplacentally, through the mambranes into the uterine circulation. In the treatment of a fetus with drugs having properties similar to diazepam, intra-amniotic administration is no better than intramuscular administration to the mother.

Adolescent↗
PubMed1997

Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases.

The present study provides a detailed kinetic analysis of diazepam metabolism by all four known members of the human P4502C subfamily expressed from their cDNAs in Escherichia coli. Both P4502C18 and P4502C19 were found to be low K(M) diazepam N-demethylases with apparent K(M) values of 24 +/- 4 microM and 21 +/- 3 microM, respectively. These values closely resemble the low K(M) component of diazepam N-demethylase activity exhibited by human liver microsomes. In addition, P4502C19 also catalyzed diazepam 3-hydroxylation with a K(M) value of 21 +/- 9 microM. Although P4502C8 was essentially inactive in catalyzing diazepam metabolism, P4502C9 catalyzed the N-demethylation with a relatively high K(M) of 80 +/- 15 microM and an overall 3- to 6-fold lower catalytic efficiency, compared with P4502C18 and P4502C19, respectively. At a substrate concentration of 10 microM, diazepam N-demethylation in a panel of human liver microsomes was inhibited 42 +/- 12% (mean +/- SD, N = 6) by a polyclonal anti-CYP2C antibody. In the same experiment, 3-hydroxylation remained unaffected (<10% inhibition). 1 microM of the CYP3A inhibitor ketoconazole inhibited 37 +/- 19% of the N-demethylation and 86 +/- 5% of 3-hydroxylation. Estimates of relative contributions to diazepam N-demethylation of P4502C9 (8 +/- 4%), P4502C18 (<2%), and P4502C19 (33 +/- 14%) and to diazepam 3-hydroxylation of P4502C19 (9 +/- 3%) based on the kinetic parameters of the recombinant enzymes and on specific contents of the individual 2C P450s determined in immunoblots are consistent with the inhibition data. In conclusion, these data confirm that both P4502C19 and P4503A are major contributors to human liver microsomal diazepam N-demethylation at low substrate concentrations, whereas P4503A is the major enzyme responsible for 3-hydroxylation.

Aged↗
PubMed1981

The effects of acute administration of diazepam on the binding of [3H]-diazepam and [3H]-gaba to rat cortical membranes.

Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed.

Animals↗
PubMed1982

Inhibitory effect of phentolamine on diazepam-induced growth hormone secretion and lack of effect of diazepam on prolactin secretion in man.

Phentolamine, a postsynaptic noradrenergic (NA) receptor blocker, inhibits diazepam-induced growth hormone (GH) secretion in man. In order to study the effect of phentolamine on six healthy subjects with a diazepam (10 mg i.v.)-induced GH increase greater than 7.5 ng/ml, it was necessary to test 11 subjects. The six diazepam GH responders showed a significantly higher (p less than 0.01) GH stimulation after diazepam alone than after diazepam plus phentolamine (60 mg i.v.). The inhibitory effect of phentolamine suggests that NA alpha receptors are involved in the diazepam-induced GH increase. Prolactin secretion after administration of diazepam (10 mg i.v.) was only slightly elevated in comparison with placebo (i.v.), suggesting that diazepam does not have an agonistic effect on dopamine (DA) receptors.

Diazepam↗
PubMed1976

Prolonged recovery after diazepam sedation: the influence of food, charcoal ingestion and injection rate on the effects of intravenous diazepam.

Thirteen subjects received diazepam 0.3 mg/kg i.v. twice with a 2-week interval between the doses. In seven subjects who had eaten at 3 h after the injection, reactive skills in a choice reaction test were impaired significantly (P less than 0.05) and there was a 20% increase in the serum diazepam concentrations at 5 h. When the meal was eaten at 7 h, a 50% increase (P less than 0.01) in the serum diazepam concentration was not associated with a significant impairment in psychomotor skills. In a second group of six subjects charcoal ingestion failed to hasten the clearance of diazepam from serum, and did not affect recovery of co-ordinative skills. In a third group of 12 subjects receiving diazepam 0.15 mg/kg i.v. twice at an interval of 2 weeks, the rapid injection of diazepam resulted in a significantly greater (P less than 0.05) degree of drooping of the upper eyelid and in a greater incidence of amnesia to abdominal pinching. The subjects also experienced more pain in the arm during the faster injection (P less than 0.01). Late effects on psychomotor skills were similar with both rates of injection. The results suggest that the remobilization of diazepam from its storage site after food intake induces a late impairment of psychomotor skills, especially if the food is eaten within less than 5 h after the injection. A rapid i.v. injection of diazepam induces greater sedative and amnesic effects than a slow injection of the same dose, but the slow injection of a greater dose is preferable because of the possibility of thrombophlebitis after rapid injection.

Absorption↗
PubMed1991

Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam.

Pharmacologic control of refractory status epilepticus has been little-studied in experimental models. In this experiment, rats in status epilepticus induced by lithium and pilocarpine were treated with MK-801 alone, diazepam alone or MK-801 plus diazepam, with treatment begun at a time when this model of status is refractory to anticonvulsant drugs. EEG samples were digitized before and for two hours after treatment, and the digitized samples subjected to computerized frequency analysis. MK-801 plus diazepam halted all manifestations of status epilepticus. Although neither MK-801 alone nor diazepam alone stopped the ongoing electrographic status epilepticus, both drugs diminished motor seizures and total EEG power. MK-801 treatment prevented the progression of changes in EEG pattern which normally occurs in this model of status epilepticus, while diazepam did not. MK-801, with and without diazepam, allowed the rats to survive the episode of status epilepticus, but rats treated with MK-801 alone required several days to recover completely, while the MK-801 plus diazepam rats appeared normal the next day. MK-801 may be a useful agent for treatment of human refractory status epilepticus, because of its neuroprotective action as well as its ability to potentiate GABAergic drugs.

Animals↗
PubMed1986

Potencies of diazepam metabolites in rats trained to discriminate diazepam.

The dose-response relationships of diazepam and several of its metabolites were determined in rats trained to discriminate diazepam (3 mg/kg) from saline in a two-lever operant choice task. Generalization of the diazepam stimulus was found to occur with temazepam and oxazepam, which were nearly equipotent with diazepam, and also with desmethyldiazepam, which was about half as potent as diazepam. The hydroxylated metabolites, 4'-hydroxydiazepam and 4'-hydroxydesmethyldiazepam were inactive in doses up to 12 mg/kg. These results show that some diazepam metabolites are quite potent behaviorally and indicate the possibility that these metabolites may contribute to the pharmacological effect of diazepam in vivo.

Animals↗
PubMed1990

Diazepam sensitive mice: differential sensitivity to the depressant and anticonvulsant effects of diazepam.

A mouse line was developed by selecting for increased sensitivity to the hypnotic effect of diazepam. These "diazepam sensitive" mice showed a mean duration of loss of righting reflex (LORR) of approximately 150 min at a dose of 20 mg/kg diazepam, this dose failed to induce LORR in the control outbred mice. Rotarod treading times of the diazepam sensitive mice were significantly shorter than that of the control mice over the same dose range indicating that these mice are also more sensitive to the sedative/muscle relaxant effects of diazepam. On the contrary, the ability of diazepam to protect against pentylenetetrazole-induced convulsion was found to be the same in the sensitive and control mice. These observations strongly suggest that the heightened sensitivity to the sedative-hypnotic effects of diazepam in the sensitive mice is unlikely to be due entirely to changes in drug disposition.

Animals↗
PubMed1989

Side-effect evaluation of a new diazepam formulation: venous sequela reduction following intravenous (i.v.) injection of a diazepam emulsion in rabbits.

Diazepam has been incorporated into a stable, submicronized injectable emulsion. Venous sequela induction in rabbits following iv administration of diazepam in a marketed hydroalcoholic solution and in the emulsion were determined and compared over a 5-day period. There was a marked difference in the local reactions induced by the iv administration of the marketed diazepam hydroalcoholic solution and the diazepam emulsion, even on the first postinjection day. This difference was confirmed by pathological analysis. The highest mean venous sequela score was reached by the rabbit group injected with the marketed diazepam solution. It should be noted that no statistical difference was observed between the saline and the diazepam emulsion rabbit groups during the 5 days of the observation period. The moderate increase in the venous sequela score values compared to that for the saline solution should be attributed to the intrinsic effect produced by diazepam itself, and not to the emulsion vehicle, which was shown not to induce any vascular reaction in the present study.

Animals↗
PubMed2002

Diazepam withdrawal-induced anxiety and place aversion in the rat: differential effects of two chronic diazepam treatment regimes.

The ability of the benzodiazepine antagonist flumazenil to precipitate a withdrawal subjective state in rats receiving chronic diazepam was investigated in a biased conditioned place aversion (CPA) procedure. Conditioning with flumazenil (10 mg/kg i.p.) in rats receiving chronic diazepam subcutaneously (s.c. in oil, 15 mg/kg/day for 28 days) but not intraperitoneally (i.p., 5 mg/kg for 28 days) resulted in the formation of a conditioned place aversion. These results indicate that precipitated withdrawal from diazepam injected s.c. but not i.p. produces a negative subjective state and that the conditioned place aversion paradigm may be useful in detecting the negative subjective effects of diazepam withdrawal. In parallel studies, the same s.c. treatment protocol produced an anxiogenic effect in the elevated plus-maze on spontaneous diazepam withdrawal, whereas rats treated with the i.p. protocol displayed no signs of withdrawal anxiety. The results of the present study are consistent with the interpretation that rats withdrawn from chronic i.p. diazepam did not demonstrate a CPA due to the 'repeated withdrawal' experiences induced by the i.p. injection route attenuating the subsequent ability of flumazenil to precipitate a subjective withdrawal state. Pharmacokinetic evidence and previous evidence showing that repeated withdrawal from diazepam in mice attenuates the aversive effects of the withdrawal experience in a conditioned taste aversion (CTA) paradigm support this interpretation.

Animals↗
PubMed1978

Serum diazepam and serum creatine kinase after intra-muscular injection of diazepam in two different vehicles.

Serum diazepam concentration and serum creatine kinase activity (serum CK) were measured in 35 patients (who were divided into three groups (A, B, and C)), over a period of 24 hours after administration of diazepam. An increase in serum CK was regarded as an indication of local muscle injury. In group A, diazepam in a polyethyleneoxydricinolate vehicle was injected intramuscularly; in group B, diazepam in a propyleneglycol-ether alcohol vehicle was injected intramuscularly; and in group C, diazepam was administered orally, combined with intramuscular administration of the vehicle used in group B. The investigation was double-blind and randomized. Serum diazepam absorption expressed as the area under the concentration curve was identical in groups A and C and significantly higher than in group B. Serum CK rose in all groups. The differences among the groups were not significant. There were considerable individual variations in all three groups, and almost half the patients showed no increase in serum CK at all. No negative correlation was found between serum diazepam and serum CK. Thus no effect of muscle injury--if present--on absorption rate could be demonstrated.

Administration, Oral↗
PubMed1980

Does diazepam pretreatment prevent succinylcholine-induced fasciculations?--a double-blind comparison of diazepam and tubocurarine pretreatments.

To determine the effectiveness of diazepam pretreatment in preventing succinylcholine-induced fasciculations, 61 surgical patients were randomly allocated into three groups receiving either diazepam (0.05 mg/kg), d-tubocurarine (0.05 mg/kg) or saline in a double-blind fashion. Following the induction of anesthesia with fentanyl and thiopental, a bolus dose of succinylcholine (1 mg/kg was injected 5 minutes after the pretreatment drugs. Resulting fasciculations were then graded visually. Responses to electrical simulation of the ulnar nerve, somatic motor responses to laryngoscopy and endotracheal intubation, and changes in serum levels of potassium were also evaluated. Diazepam had no effect on frequency or intensity of succinylcholine fasciculations. Fasciculations were observed in 90% of the patients given placebo injections and in 95% of those given diazepam, but in only 16% of those given tubocurarine. Tubocurarine prolonged the onset and shortened the duration of the succinylcholine block and thus made intubation more difficult. Diazepam accelerated onset, but had no effect on duration of succinylcholine block. The twitch response following ulnar nerve stimulation disappeared after 84 seconds (p < 0.01 vs placebo) in patients given diazepam after 115 seconds in patients given tubocurarine, and after 106 seconds in those given placebo injections. The increase in serum potassium after succinylcholine was prevented by pretreatment with d-tubocurarine but not by diazepam.

Clinical Trials as Topic↗
PubMed1983

Pharmacokinetic model for diazepam and its major metabolite desmethyldiazepam following diazepam administration.

A five-compartment open model was used to simulate the blood concentration profiles of diazepam and its metabolite, desmethyldiazepam, following single- and multiple-dose administrations of diazepam. The parameter estimates for diazepam were previously reported literature values. The parameters estimates for the metabolite were calculated from literature values of blood concentrations of desmethyldiazepam following the administration of clorazepate. The five-compartment open model suggests that approximately 50% of the administered diazepam is biotransformed to desmethyldiazepam, and that the elimination profile of the metabolite is not altered by the presence of the drug. The model may also be readily adapted to predict the concentrations of diazepam and desmethyldiazepam in cerebrospinal fluid following the administration of diazepam by simply correcting the blood or plasma concentrations of the drug and metabolite for the degree of plasma protein binding.

Adult↗