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PubMed2000

The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam.

The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.

Amygdala↗
PubMed2003

Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice.

RATIONALE: Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety. OBJECTIVE: The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and the parameters of benzodiazepine receptors in mice lacking CCK2 receptors. METHODS: The action of diazepam (0.5-3 mg/kg i.p.) was studied in the elevated plus-maze model of anxiety and rotarod test using mice lacking CCK2 receptors. The parameters of benzodiazepine receptors were analysed using [3H]-flunitrazepam binding. RESULTS: In the plus-maze test, the exploratory activity of the homozygous (-/-) mice was significantly higher compared to their wild-type (+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam. Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice. A similar effect in the homozygous (-/-) mice was established after the administration of diazepam 1 mg/kg. The highest dose of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (-/-) animals suppression of locomotor activity was evident. The performance of the homozygous (-/-) mice in the rotarod test did not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous (-/-) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment of motor co-ordination in the homozygous (-/-) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (-/-) mice. CONCLUSIONS: Female mice lacking CCK2 receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (-/-) mice probably explains why the administration of a higher dose of diazepam is necessary to induce an anxiolytic-like action in these animals. The highest dose of diazepam (3 mg/kg) induced significantly stronger suppression of locomotor activity and impairment of motor co-ordination in the homozygous (-/-) mice compared to the wild-type (+/+) littermates. The increase in the action of diazepam is probably related to the elevated density of benzodiazepine receptors in the cerebellum of homozygous (-/-) mice. The present study seems to be in favour of increased tone of the GABAergic system in mice without CCK2 receptors.

Animals↗
PubMed1993

Flumazenil induces localised increases in glucose utilization during diazepam withdrawal in rats.

The quantitative [14C]2-deoxyglucose autoradiographic technique has been employed to identify the neural circuits involved in diazepam withdrawal. Local cerebral glucose utilization (LCGU) was assessed in parallel groups of rats chronically treated with diazepam (5 mg/kg i.p., daily for 28 days), in rats that were withdrawn from chronic diazepam 24 h previously and in those that received flumazenil (5 mg/kg i.v.) immediately or 24 h after the last dose of diazepam. Two further groups received chronic vehicle or acute flumazenil (5 mg/kg i.v.). Rats withdrawn from diazepam 24 h previously did not produce changes in LCGU in the 51 structures examined compared with both control and chronic diazepam treated groups, suggesting that spontaneous withdrawal from small doses of diazepam does not evoke marked alterations in functional activity. In contrast, flumazenil-precipitated diazepam withdrawal produced a marked increase in glucose use in structures of the Papez circuit of emotion (mammillary body, anterior thalamus, cingulate cortex), together with increases in the septal nucleus, basolateral amygdala and nucleus accumbens. Less widespread increases in glucose use occurred in primary auditory and visual areas and in extrapyramidal areas. This pattern resembles that produced after acute FG-7142 administration (Brain Res., 475 (1988) 218-231). In rats receiving flumazenil 24 h after the last dose of diazepam there was a similar, but more restricted, pattern of change in LCGU. Flumazenil had no effect on LCGU in drug naive rats. Thus, flumazenil could only exert an effect upon LCGU in rats chronically treated with diazepam. These data provide functional neuroanatomical evidence for a withdrawal shift in the inverse agonist direction after chronic diazepam and suggest that flumazenil-precipitated withdrawal changes may merely be a reflection of this phenomenon.

Animals↗
PubMed1982

Ro 15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital.

The benzodiazepine antagonist properties of Ro 15-1788 were evaluated in rats trained to discriminate between saline and either 1.0 mg/kg of diazepam or 10 mg/kg of pentobarbital in a two-choice discrete-trial shock avoidance procedure. When administered alone, 1.0 mg/kg of diazepam and 10 mg/kg of pentobarbital produced comparable amounts of drug-appropriate responding (less than 84%), whether rats were trained to discriminate between diazepam or pentobarbital and saline. Ro 15-1788 (3-32 mg/kg, p.o.), administered 10 min before diazepam or pentobarbital, produced a dose-related blockade of the discriminative effects of diazepam in both groups of rats, but was completely ineffective in blocking the discriminative effects of pentobarbital. The dose-effect curve for the discriminative effects of diazepam was shifted to the right in a parallel fashion 3- and 13-fold by 10 and 32 mg/kg of Ro 15-1788, respectively, indicating that Ro 15-1788 acts as a surmountable, competitive antagonist of diazepam. When administered alone, Ro 15-1788 (32-100 mg/kg, p.o.) produced primarily saline-appropriate responding, although 100 mg/kg of Ro 15-1788 produced drug-appropriate responding in one out of eight rats. When administered orally 30 min after diazepam, Ro 15-1788 (32 mg/kg) completely reversed within 10 min the discriminative effects of diazepam. The blockade of diazepam's discriminative effects by 32 mg/kg of Ro 15-1788 appeared to last at least as long (approximately 2 hr) as the effects of diazepam alone.

Animals↗
PubMed1985

The inhibitory effect of diazepam on defensive burying: anxiolytic vs. analgesic effects.

The hypothesis that analgesic mechanisms might account for the suppressive effect of diazepam on defensive burying was tested in four experiments. In the first experiment, 1 mg/kg of diazepam had no appreciable effect on rat's latency to escape from a painful heat stimulus, but reliably suppressed defensive burying behavior. There was no significant relationship between the diazepam-treated rats' latency to escape and their duration of burying. Rats in Experiment 2 were injected with diazepam during a delay between shock and testing, so that they could not be experiencing the putative analgesic effect of diazepam during the shock. In spite of this, diazepam produced a significant suppression of burying compared to saline control. In the next experiment, the effect of diazepam on defensive burying was assessed in the complete absence of painful stimulation by exposing the rats to a novel stimulus known to elicit burying behavior. Diazepam suppressed burying behavior to the novel stimulus in a dose-dependent fashion. Finally, the ability of 10 mg/kg of naloxone to reverse the suppressive effect of 1 mg/kg of diazepam was assessed in Experiment 4. Naloxone failed to reverse the suppressive effect of diazepam and had no significant effect on defensive burying by itself, suggesting that the modulating influence of diazepam on rats' defensive burying behavior did not depend upon endogenous opiate mechanisms. Taken together, the results of the four experiments did not support the view that benzodiazepines produce their anxiolytic effects through analgesic mechanisms.

Analgesics↗
PubMed1992

Neuroleptic-induced changes in the anxiolytic and myorelaxant properties of diazepam in the rat.

Diazepam (2.0 mg/kg) was injected (IP) into rats 30 min before chlorpromazine (2.5, 5.0, or 10.0 mg/kg) on ten occasions. All doses of chlorpromazine enhanced the capacity of diazepam to increase rats' exploration of the exposed arms of an elevated plus-maze, an animal screening test for anxiolytic and anxiogenic substances. When maze testing occurred during each of the ten diazepam----chlorpromazine trials (after diazepam but before chlorpromazine), this enhancement effect appeared on Trial 6 and persisted thereafter. Haloperidol (3.0 mg/kg, IP) changed diazepam-elicited plus-maze activity in the same manner as chlorpromazine; however, thioridazine (10.0 mg/kg) and pimozide (2.0 mg/kg) were ineffective. Additionally, haloperidol, like chlorpromazine, was found to reduce diazepam's muscle relaxation effect (inclined plane test) as a consequence of diazepam----haloperidol pairings; once again, thioridazine and pimozide proved ineffective. These results suggested that not all neuroleptics will alter diazepam activity, and also that dopamine blockade per se is not sufficient to induce such changes. While the reasons for the enhanced plus-maze effects of diazepam induced by haloperidol and chlorpromazine remain elusive, the diminished myorelaxant effect may be linked to a neuroleptic's capacity to induce muscular side effects: thioridazine and pimozide are far less likely to yield such effects than are chlorpromazine and haloperidol. Haloperidol administered chronically by itself was found to have an effect on diazepam-induced myorelaxation. Administration of this butyrophenone either orally (2.0 mg/kg daily for 22 days) or in depot form (haloperidol decanoate, 60.0 mg/kg IM once a month for four months) caused a diminished effect of diazepam in rats subjected to the inclined plane test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The effect of acute and chronic diazepam treatment on stress-induced changes in cortical dopamine in the rat.

The mesocortical dopamine system is thought to play an important role in the etiology of the stress response. Dopamine (DA) has been shown to accumulate in the rat frontal cortex in response to a wide variety of stressors. Diazepam, an anxiolytic benzodiazepine, can reverse the effects of stress on cortical DA. We investigated the effects of acute and chronic diazepam administration on immobilization stress-induced changes of the DA system in the frontal cortex of the rat. In the first study, 2.5 mg/kg diazepam was administered 20 min prior to 40 min of immobilization stress. Acute diazepam significantly reduced basal levels of extracellular DA and antagonized the stress-induced increase in cortical DA when compared to untreated stressed rats. Acute diazepam did not significantly effect extracellular DOPAC. In the second study, an experimental group of rats was given approximately 2 mg/kg/day diazepam in their drinking water for 3 weeks. This treatment significantly reduced anxiety as assessed by a staircase test for anxiety. Chronic diazepam had no effect on basal levels of cortical DA. However, chronic diazepam treatment also attenuated stress-induced increases in extracellular DA when compared to untreated stressed control rats. Chronic diazepam did not affect stress-induced changes in DOPAC but it did antagonize the effects of stress on HVA. Thus, acute and chronic diazepam treatment can antagonize stress-induced activation of the mesocortical DA system. It is proposed that this effect is produced through an enhancement of GABAergic neurotransmission by diazepam. The role of the dopaminergic system during stress, anxiety, and schizophrenia is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils.

The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia. Excitotoxicity is widely thought to contribute to this cell death. Accordingly, drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is neuroprotective. Most studies fail to adequately control for this confound. In this study, we tested whether diazepam reduces injury in temperature controlled gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether diazepam augments hypothermic neuroprotection. All gerbils were implanted with a core temperature telemetry probe and a cannula for the subsequent insertion of a thermocouple probe to measure ischemic brain temperature. Subsequently, they were given a 5-min normothermic ischemic insult. In Experiment 1, two groups of gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post-ischemia. Temperature was maintained in one group by heating lamps. Another group was administered saline. Diazepam reduced cell death at 7 days post-ischemia when the drug-induced hypothermia was permitted, but not when it was prevented. In Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post-ischemia with prolonged hypothermia, diazepam and the combination or saline treatment. Hypothermia, but not diazepam, provided partial neuroprotection and diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with diazepam is solely due to hypothermia. These data do not support the clinical use of diazepam as a neuroprotectant after global ischemia.

Animals↗
PubMed2006

Diazepam effects on carrageenan-induced inflammatory paw edema in rats: role of nitric oxide.

High doses of diazepam (10.0-20.0 mg/kg) were shown to reduce the volume of acute inflammatory paw edema in rats as a response to carrageenan administration. This effect was attributed to an action of diazepam on the peripheral-type benzodiazepine receptor (PBR) present in the adrenal and/or immune/inflammatory cells. The present study was undertaken to analyze the involvement of nitric oxide (NO) on the effects of diazepam on carrageenan-induced paw edema in rats (CIPE) and to look for the presence of PBR and inducible/constitutive NO synthases (NOS) on slices taken from the inflamed paws of diazepam-treated rats. For that, an acute inhibition of NO biosynthesis was achieved using 50.0 mg/kg No mega-nitro-L-arginine (L-NAME), L-arginine (300.0 mg/kg), the true precursor of NO, and D-arginine (300.0 mg/kg), its false substrate, were also used. The following results were obtained: (1) diazepam (10.0 and 20.0 mg/kg) decreased CIPE values in a dose- and time-dependent way; (2) diazepam effects on CIPE were increased by L-NAME pretreatment; (3) treatment with L-arginine but not with D-arginine reverted at least in part the decrements of CIPE values observed after diazepam administration; (4) PBR were found in endothelial and inflammatory cells that migrated to the inflammatory site at the rat paw; (5) confocal microscopy showed the presence of both PBR and NOS in endothelial and inflammatory cells taken from inflamed paw tissues of rats treated with diazepam a finding not observed in tissues provided from rats treated with diazepam's control solution. These results suggest an important role for NO on the effects of diazepam on CIPE. Most probably, these effects reflect a direct action of diazepam on PBR present in the endothelium of the microvascular ambient and/or on immune/inflammatory cells. An action like that would lead, among other factors, to a decrease in NO, generated by NO synthase, and thus in the mechanisms responsible for CIPE.

Animals↗
PubMed1999

Sensitization by chronic diazepam treatment of A2A adenosine receptor-mediated relaxation in rat pulmonary artery.

The effects of a 10-day i.p. treatment of rats with diazepam on responses to subtype selective adenosine receptor agonists were studied 3 h, 2 and 8 days after termination of diazepam treatment in isolated cardiovascular tissues possessing distinct adenosine receptors. After long-lasting diazepam exposure, the relaxation elicited by the specific A2A receptor agonist CGS 21680 was enhanced in rat main pulmonary arteries (a tissue containing A2A adenosine receptors). The increased sensitivity of A2A receptors observed 3 h and 2 days after withdrawal of diazepam was completely restored by the 8th day of the wash-out period. N6-cyclopentyladenosine (CPA)-induced suppression in mechanical activity of electrically stimulated rat atrial myocardium (a tissue containing A1 adenosine receptors) was not altered following diazepam treatment. In order to reveal the possible role of inhibition of membrane adenosine transport in the effects of diazepam (a moderate inhibitor of membrane adenosine transport), the action of a 10-day treatment with dipyridamole or S-(p-nitrobenzyl)-6-thioinosine (NBTI; prototypic adenosine uptake inhibitors) was also studied. Dipyridamole or NBTI treatment, like diazepam, increased the responsiveness of rat pulmonary artery to CGS 21680, but did not influence the cardiodepressive effect of CPA in electrically driven left atrial myocardium. The CGS 21680-induced relaxations were significantly antagonized by 10 nM ZM 241385 (a selective A2A adenosine receptor antagonist) in vessels of diazepam-treated rats. The relaxation responses to verapamil were unaltered in pulmonary arteries obtained from animals chronically treated with diazepam, dipyridamole or NBTI. These results suggest that chronic diazepam treatment is able to enhance the A2A adenosine receptor-mediated vascular functions, but does not modify the responses mediated via A1 receptors of rat myocardium, where nucleoside transport inhibitory sites of membrane are of a very low density. It is possible that sensitization of A2A adenosine receptor-mediated vasorelaxation is due to a long-lasting inhibition of membrane adenosine transporter during diazepam treatment.

Adenosine↗
PubMed2004

Effect of diazepam on adenosine 3',5'-cyclic monophosphate (cAMP) plasma levels in anesthetized patients.

BACKGROUND: It has been previously demonstrated that diazepam inhibits the cyclic nucleotide phosphodiesterase type 4 isozyme (PDE4). PDE enzymes mediate the hydrolysis of the nucleotide adenosine 3',5'-cyclic monophosphate (cAMP). OBJECTIVE: The aim of this study was to determine whether IV administration of diazepam affects cAMP plasma levels in anesthetized patients. METHODS: In this prospective study, patients scheduled to undergo elective myocardial revascularization surgery with anesthetization with etomidate (0.3 mg/kg), fentanyl (total dose 20-25 microg/kg), and cisatracurium (150 microg/kg), supplemented with sevoflurane (2% in an oxygen/air mixture), were randomly assigned to 1 of 3 groups to receive diazepam (0.28 mg/kg IV), diazepam vehicle (alcohol and propylene glycol IV), or saline. Before the start of the surgical procedure, at 5 and 10 minutes after administration of diazepam, vehicle, or saline, blood samples were obtained for determination of the diazepam, cAMP, and catecholamine levels. RESULTS: Ten patients received diazepam, 10 received vehicle, and 5 received saline. The mean (SEM) arterial serum concentrations of diazepam were 2.1 (0.2) microg/mL and 1.1 (0.4) microg/mL, respectively, at 5 and 10 minutes after administration. cAMP plasma levels increased from mean (SEM) baseline values of 30.0 (1.7) nmol/L to 35.5 (1.5) nmol/L (P < 0.05) and 43.1 (1.7) nmol/L (P < 0.05) at 5 and 10 minutes, respectively, after diazepam administration. No significant changes in cAMP plasma levels were observed compared with the mean (SEM) baseline value of 32.0 (1.7) nmol/L at 5 minutes (31.8 [1.3] nmol/L) and 10 minutes (30.9 [1.4] nmol/L) after vehicle administration. Epinephrine plasma concentration increased from a mean (SEM) baseline value of 0.13 (0.02) ng/mL to 0.22 (0.02) ng/mL (P < 0.05) at 10 minutes after administration of vehicle and 0.21 (0.02) ng/mL (P < 0.05) at 10 minutes after administration of diazepam. CONCLUSION: In this preliminary study, diazepam increased cAMP plasma levels in anesthetized patients, presumably through inhibition of PDE4 activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor.

1. The responses of the electrically-driven right ventricle strip of the guinea-pig heart to diazepam were recorded in the absence and in the presence of different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors. 2. Diazepam, at concentrations ranging from 1 microM to 100 microM, was devoid of effect on the contractile force in this preparation. 3. Conversely, diazepam (5 microM-100 microM) produced a consistent positive inotropic response in the presence of a concentration (1 microM), that was without effect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram. 4. This effect of diazepam was not gamma-aminobutyric acid (GABA)-dependent, since it was neither mimicked nor potentiated by GABA, and was not affected by either a high concentration (5 microM) of the antagonists of the benzodiazepine/GABA/channel chloride receptor complex, picrotoxin, flumazenil and beta-carboline-3-carboxylic acid methyl ester (betaCCMe), or by the inverse agonists, beta-carboline-3-carboxylic acid N-methylamide (betaCCMa) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM, 0.1 microM). Furthermore, a specific antagonist of the peripheral benzodiazepine receptors, PK 11195 (5 microM), did not influence the effect of diazepam. 5. Biochemical studies with isolated PDEs, confirmed that diazepam selectively inhibits type 4 PDE from guinea-pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non-competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP specific PDE absent from cardiac muscle, with a potency close to that shown for PDE 4. 6. Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high affinity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea-pig eosinophils, where only type 4 PDE is present. 7. The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally-related benzodiazepines, that also displaced [3H]-rolipram from its high affinity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site. 8. The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this effect seems neither to be mediated by the benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Reduction of acute inflammation in rats by diazepam: role of peripheral benzodiazepine receptors and corticosterone.

Carrageenin causes a reproducible inflammatory reaction and remains the standard irritant for examining acute inflammation and anti-inflammatory drugs. High doses of diazepam (10.0-20.0 mg/Kg) were shown to reduce the volume of acute inflammatory paw edema in rats as a response to carrageenin administration. The present experiment was undertaken to investigate the possible roles of peripheral-type benzodiazepine receptors (PBRs) and corticosterone on the anti-inflammatory effects of diazepam. Five experiments were conducted to assess the effects of a single dose (10.0 mg/Kg) of diazepam on carrageenin-induced paw edema (CIPE), pleurisy and increase in vascular permeability in rats. Results showed that: 1. diazepam or Ro5-4864 (a PBR agonist) treatment reduced CIPE values; 2. prior treatment with PK11195 (a non-benzodiazepine PBR antagonist) suppressed the effects of either diazepam or Ro5-4864 on CIPE; 3. diazepam reduced the volume of the pleural exudate in carrageenin-injected rats, as well as its leukocyte count; 4. diazepam treatment reduced the magnitude of the increase in vascular permeability caused by carrageenin; 5. adrenalectomy suppressed the effects of diazepam on CIPE; and 6. diazepam treatment increased the serum concentration of corticosterone. These results suggest a relevant role of PBR and corticosterone on diazepam-induced changes in inflammation. They are discussed in the light of a possible activation of mitochondrial PBRs within the adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE.

Acute Disease↗
PubMed1996

In-vivo study of diazepam transfer across the first trimester human placenta.

Diazepam transfer by the first trimester human placenta was investigated at pregnancy termination between 6 and 12 weeks of gestation. Fetal fluid samples were obtained from the exocoelomic and amniotic cavities of 65 pregnancies between 8 and 25 min following the i.v. administration of 0.1 mg/kg diazepam to the mother. Diazepam was detected in one-third of coelomic fluid samples and two-thirds of amniotic fluid samples. Maternal serum and urine diazepam concentrations correlated negatively and positively respectively, with time from drug injection to sampling. Individual diazepam concentrations were low on the fetal side, and the corresponding concentrations were independent of maternal serum concentrations and the time from drug injection to sampling. Amniotic fluid diazepam content increased significantly with advancing gestational age. A multiple regression analysis showed that the diazepam content of the coelomic fluid was not influenced by maternal serum diazepam concentration, the time from drug injection to sampling or gestational age, whereas only gestational age contributed to the diazepam content of amniotic fluid. These data demonstrate that the placental transfer of diazepam occurs from week 6 of gestation, indicate a preferential transfer of this drug to the amniotic cavity and suggest that diazepam may accumulate in fetal circulation and tissues during organogenesis.

Adult↗
PubMed1980

Diurnal variations in plasma diazepam concentrations associated with reciprocal changes in free fraction.

1 The characteristics and mechanism of fluctuations in diazepam and N-desmethyldiazepam concentrations and diazepam free fraction were studied in six volunteers, who received diazepam (10 mg, i.v. over 20 min) and in five chronic diazepam users. 2 Within a day total diazepam and N-desmethyldiazepam concentrations varied significantly (P less than 0.001) and were lower than predicted between 23.00 and 08.00 h and higher by 09.00 h. In contrast, diazepam free fraction also varied significantly (P less than 0.001) and was highest between 23.00 and 08.00 h and lower by 09.00 h. Coincident increases in total diazepam concentrations (P less than 0.005) and decreases in diazepam free fraction were associated with food intake (P less than 0.05). 3 The coincident diurnal variations in diazepam and N-desmethyldiazepam concentrations and the negative correlation between total diazepam concentration and diazepam free fraction (r = 0.73, P less than 0.001) suggest that the mechanism of the fluctuations is intravascular and tissue redistribution rather than effect on drug biotransformation. 4 These variations may introduce large between and within investigator experimental differences in the determination of kinetic parameters. Free drug concentration varies over the day, and within day variations in clinical effect may be observed.

Adolescent↗
PubMed1981

The influence of intramuscularly administered pethidine on the amnesic effects of intravenous diazepam during intravenous regional anaesthesia.

Patients undergoing surgery under regional anaesthesia often receive narcotic analgesics for premedication which may modify the sedative and amnesic effects of intravenously administered diazepam. Sixty-two patients scheduled for upper extremity surgery under intravenous regional anaesthesia received 0.15 mg/kg of diazepam intravenously to supplement the local anaesthesia. Thirty-two of the patients received 0.01 mg/kg of atropine plus 1 mg/kg of pethidine and 30 patients only atropine intramuscularly approximately 1 h before injection of diazepam. Another 30 patients received the same atropine-pethidine premedication and saline intravenously, and served as a reference group. Atropine-pethidine premedication followed by saline did not produce any amnesic effects. Sixty-nine and 38% of patients receiving atropine-pethidine premedication followed by diazepam did not remember a picture shown to them 15 min after diazepam injection or the performance of operation, respectively, the respective figures for patients given atropine premedication followed by diazepam being only 23% and 0% (P less than 0.01 - 0.001 between groups). The anti-recall of painful stimulus (exanguination) was significantly (P less than 0.01) more common when diazepam was given after pethidine premedication (31%) when compared to its injection after atropine alone (7%). The drowsiness produced by the drugs was greatest and the overall patient acceptability of the technique used most satisfactory when pethidine was used for premedication and diazepam for sedation. It is concluded that intramuscularly administered pethidine potentiates the amnesic action of intravenous diazepam for painful stimuli, prolongs the amnesic action of diazepam for visual stimuli and improves the patients' acceptability of intravenous regional anesthesia supplemented by intravenous diazepam.

Adult↗
PubMed2004

The role of diazepam in the treatment of nerve agent poisoning in a civilian population.

The main site of action of diazepam, as with other benzodiazepines, is at the GABA(A) receptor, although it has been suggested that some of the potentially beneficial actions of diazepam in nerve agent poisoning are mediated through other means. It is likely that convulsions may have long-term sequelae in the central nervous system, because of damage by anoxia and/or excitotoxicity. Numerous pharmacodynamic studies of the action of diazepam in animals experimentally poisoned with nerve agents have been undertaken. In nearly all of these, diazepam has been studied in combination with other antidotes, such as atropine and/or pyridinium oximes, sometimes in combination with pyridostigmine pretreatment. These studies show that diazepam is an efficacious anticonvulsant in nerve agent poisoning. There is considerable experimental evidence to support the hypothesis that diazepam (and other anticonvulsants) may prevent structural damage to the central nervous system as evidenced by neuropathological changes such as neuronal necrosis at autopsy. In instances of nerve agent poisoning during terrorist use in Japan, diazepam seems to have been an effective anticonvulsant. Consequently, the use of diazepam is an important part of the treatment regimen of nerve agent poisoning, the aim being to prevent convulsions or reduce their duration. Diazepam should be given to patients poisoned with nerve agents whenever convulsions or muscle fasciculation are present. In severe poisoning, diazepam administration should be considered even before these complications occur. Diazepam is also useful as an anxiolytic in those exposed to nerve agents.

Adult↗
PubMed1990

[The effect of RO15-1788 on the interaction between pancuronium and diazepam].

Some reports have shown that diazepam potentiates the neuromuscular blocking effect of pancuronium in in vitro experiments. Another report shows that a receptor for diazepam is present in the rat diaphragm and there is a direct blocking effect by diazepam of the neuromuscular junction of diaphragm muscle. Such interaction, consequently, may be related to the peripheral diazepam receptor. Based on such a hypothesis, RO15-1788, a recently developed diazepam antagonist, was used in an attempt to clarify the mechanism of such interaction. Hemidiaphragm preparations were immersed in an organ bath filled with Krebs solution which was bubbled with 95% oxygen and 5% carbon dioxide at 37 degrees C. The phrenic nerves were stimulated supramaximally at 0.1 Hz intervals. Mechanical twitch responses were recorded. The preparations were divided into five groups (group 1: treated with only 30 microM of diazepam, group 2: treated with 30 microM of diazepam and 3.0 microM of RO15-1788, group 3: treated with 30 microM of diazepam and 4.0 microM of RO15-1788, group 4: treated with 30 microM of diazepam and 6.6 microM of RO15-1788, group 5: without diazepam and RO15-1788). Cumulative dose-response curves were determined for pancuronium, and ED50 was calculated from each of the 5 curves. There was almost no effect of RO15-1788 in group 2, but RO15-1788 increased ED50 for 20% in group 3 (ED50 3.04 +/- 0.10 microM) and for 35% in group 4 (ED50 3.12 +/- 0.07 microM), respectively, as compared with group 1 (ED50 2.76 +/- 0.08 microM). This phenomenon shows that diazepam was antagonized significantly by RO15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)

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