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PubMed1989

Rectal diazepam in pediatric status epilepticus.

Status epilepticus is a neurologic emergency with an 8% to 12% mortality. Rapid ablation of seizure activity is imperative. Although intravenous administration of diazepam is the preferred immediate treatment, vascular access is often difficult to achieve. Rectal administration of diazepam is easily accomplished during status epilepticus. Five cases in which diazepam administered in the rectal lumen stopped seizure activity are reported. Rectal diazepam appears to be safe and efficacious. It should be considered as an alternate to intravenous therapy when immediate vascular access is delayed. Rectal diazepam may have great benefit in the prehospital setting.

Administration, Rectal↗

PubMedDate not supplied

Ethanol and diazepam interactions on conflict behavior in rats.

Twenty-four adult male rats trained on the Geller-Seifter conflict procedure received: 1.0, 2.0, or 4.0 mg/kg diazepam at 15 min, 0.25, 0.5, 1.0, 2.0, or 4.0 g/kg of ethanol (EtOH) at 30 min prior to the test session, or combinations of the same diazepam doses and 0.5 g/kg of EtOH. Ethanol administration produced a significant (p less than 0.05) dose-related decrease in lever pressing during the periods prior to the introduction of the tone stimulus, compared to lever pressing during the corresponding control periods on the day prior to drug treatment. During the posttone periods 0.25 g/kg increased lever pressing (p less than 0.05), while doses of EtOH from 0.5 to 4.0 g/kg resulted in significantly lower levels of lever pressing in periods following the discontinuation of the tone. In the presence of the conflict evoking tone stimulus, rats treated with 2.0 g/kg of EtOH increased their rate of lever pressing, while animals receiving the other EtOH doses exhibited lever pressing comparable to that observed during the corresponding control periods. Administration of EtOH had no effect on the number of reinforcements received during the entire test session, except for a significant (p less than 0.05) reduction at the highest dose of 4.0 g/kg. Diazepam increased the number of reinforcements received during the entire test session as compared to those obtained during control sessions. Lever pressing was not affected by diazepam treatment during pretone or tone periods. During the posttone periods responses were significantly (p less than 0.05) increased in rats receiving the lowest dose of 1.0 mg/kg of diazepam but the other doses were without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Chronic treatment with diazepam or the inverse benzodiazepine receptor agonist FG 7142 causes differential changes in the effects of GABA receptor stimulation.

Daily treatment of mice with diazepam leads to the development of tolerance to the anxiolytic and anticonvulsant effect of the benzodiazepine, while daily treatment with the proconvulsant benzodiazepine receptor inverse agonist FG 7142 produces sensitization to its effects in that seizures develop (chemical kindling). In the present study, the effects of GABA receptor stimulation were studied 2 days after termination of 13 days treatment with diazepam, 20 mg/kg i.p./day, and FG 7142, 40 mg/kg i.p./day. For GABA receptor stimulation, the GABA agonist progabide was chosen because among several GABA receptor stimulants tested it was the only compound that induced increases in seizure threshold in non-toxic doses. Using the threshold for maximal (tonic extension) electroconvulsions as a measure for anticonvulsant efficacy, the anticonvulsant effect of progabide (100 mg/kg i.p.) was unchanged after chronic treatment with diazepam but was lost in FG 7142 kindled animals. Conversely, the hypothermic effect of progabide was reduced after treatment with diazepam but not with FG 7142. Baseline seizure threshold was unchanged 2 days after chronic administration of diazepam but increased in the FG 7142 pretreated mice. The data indicate that tolerance to benzodiazepines and kindling by FG 7142 are associated with different changes in GABA receptor function.

Animals↗

PubMed1992

Repeated anticonvulsant testing: contingent tolerance to diazepam and clobazam in kindled rats.

The acute anticonvulsant efficacy of diazepam (1.5 mg/kg, i.p.) was evaluated by repeated test injection in kindled rats subcutaneously implanted with diazepam-filled or empty silastic tubes for 3 weeks. Tolerance developed to acute test injections in both diazepam- and sham-implanted rats. Tolerance developed to a lesser extent in another group of diazepam-implanted rats which did not receive acute intermittent anticonvulsant tests. The hypothesis that contingent tolerance had developed to the anticonvulsant actions of benzodiazepines (diazepam, 1.5 mg/kg, i.p. and clobazam, 10 mg/kg, i.p.) in kindled rats given acute intermittent injections was investigated using a 'before-after' design. Significant contingent tolerance developed in rats which received intermittent benzodiazepine treatment before, but not after, amygdala stimulation. Tolerance developed to different extents depending on the seizure measure evaluated (forelimb clonus duration, amygdala afterdischarge duration, motor seizure latency and duration, and seizure stage). Contingent tolerance to both benzodiazepines developed at a similar rate. The findings suggest that contingent tolerance may contribute a sizeable component to the overall functional benzodiazepine tolerance measured in long-term anticonvulsant drug studies in kindled rats. Several questions regarding contingent tolerance phenomena are posed and the implications of these findings for studies using repeated anticonvulsant testing are discussed.

Animals↗

PubMed1992

Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.

A series of 5 generalized tonic-clonic seizures within 30 min was induced by repeated transauricular electrical stimulation in mice. In this model, the anticonvulsant potency of intravenous valproate was compared with diazepam and phenytoin. All 3 drugs proved capable of rapidly suppressing the seizures after intravenous bolus injection. Potent anticonvulsant activity of diazepam and valproate was already obtained after 30 s, while phenytoin's onset of action was somewhat slower. In contrast to diazepam, valproate and phenytoin suppressed the seizures at non-sedative doses. ED50s for blockade of generalized tonic-clonic seizures throughout the 30-min period of repeated electrical stimulation were 6.6 mg/kg for diazepam, 28 mg/kg for phenytoin and 212 mg/kg for valproate. Determination of valproate in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. The data indicate that an intravenous formulation of valproate might be a useful alternative to phenytoin as a non-sedative anticonvulsant for diazepam-resistant status epilepticus.

Animals↗

PubMed2006

Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats.

Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects similar to diazepam in animal models of innate aversive behavior. However, the effects of CBD contextual conditioned fear have not been studied. Therefore, the aim of this work was to compare the behavioral and cardiovascular effects of CBD and diazepam, a prototype anxiolytic, in animals submitted to a contextual conditioned fear paradigm. Male Wistar rats were submitted to a 10min conditioning session (six footshocks, 2.5 mA, 3s, delivered at pseudo-random intervals). The behavioral and cardiovascular responses to the context were measured 24h later in a 10 min test session. Diazepam (2.5 mg/kg), FG-7142 (8 mg/kg), a benzodiazepine inverse agonist, or CBD (10 mg/kg) were administered i.p. before the test session. Conditioned rats submitted to the aversive context exhibited more freezing behavior and a larger increase in blood pressure and heart rate as compared to non-conditioned animals. These effects were attenuated by CBD and diazepam in the conditioned animals. These drugs did not have any effect in non-conditioned rats. FG-7142 treatment failed to change the behavioral and cardiovascular responses to the aversive context. In conclusion, the results suggest that CBD has anxiolytic-like properties similar to those of diazepam in a rat model of conditioned fear to context.

Analysis of Variance↗

PubMed2004

MK-801 prevents the increased NMDA-NR1 and NR2B subunits mRNA expression observed in the hippocampus of rats tolerant to diazepam.

The chronic diazepam administration in rats has been show from our previous results, to produce an increased synaptic plasticity. Furthermore, this occurs with a concomitant over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits. MK-801, a non-competitive antagonist of N-methyl-D-aspartate receptor, impairs both the development of conditioned tolerance to diazepam and the hippocampal long-term potentiation generation. In the present study, we have further investigated the hippocampal glutamatergic transmission in the development of tolerance to diazepam. Our results demonstrate that the development of tolerance to the hypolocomotive effect of diazepam, along with the increased hippocampal synaptic plasticity and the associated over expression of the mRNA NR1 and NR2B N-methyl-D-aspartate receptor subunits, were blocked by previous MK-801 administration. We suggest that the participation of hippocampal glutamatergic transmission is relevant to increased hippocampal synaptic plasticity, the latter being a neurobiological mechanism behind the development of the conditioned tolerance to diazepam.

Analysis of Variance↗

PubMed2005

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.

OBJECTIVES: Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. METHODS: Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. RESULTS: CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). CONCLUSION: We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.

Actins↗

PubMed2005

Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency.

Diazepam is a benzodiazepine used in the treatment of anxiety, insomnia and seizures, but with the potential for abuse. Like the other benzodiazepine anxiolytics, diazepam does not increase dopamine in the nucleus accumbens. This raises the question as to which other neurotransmitter systems are involved in diazepam dependence. The goal was to monitor dopamine and acetylcholine simultaneously following acute and chronic diazepam treatment and after flumazenil-induced withdrawal. Rats were prepared with microdialysis probes in the nucleus accumbens and given diazepam (2, 5 and 7.5 mg/kg) acutely and again after chronic treatment. Accumbens dopamine and acetylcholine decreased, with signs of tolerance to the dopamine effect. When these animals were put into the withdrawal state with flumazenil, there was a significant rise in acetylcholine (145%, P<0.001) with a smaller significant rise in dopamine (124%, P<0.01). It is suggested that the increase in acetylcholine release, relative to dopamine, is a neural component of the withdrawal state that is aversive.

Acetylcholine↗

PubMed2004

Polarographic determination of diazepam with its parallel catalytic wave in the presence of persulfate.

A new method for the determination of diazepam was proposed based on its polarographic catalytic wave in the presence of persulfate. In 0.20 M NaAc-HAc (pH 4.7)-1.0 x 10(-2) M K(2)S(2)O(8) supporting electrolyte, the reduction wave of diazepam with peak potential -0.89 V (versus SCE) was catalyzed, producing a parallel catalytic wave. The peak current of the catalytic wave was 15 times higher than that of the corresponding reduction wave for 4.0 x 10(-6) M diazepam, and was rectilinear to diazepam concentration in the range of 5.6 x 10(-8) to 8.9 x 10(-6) and 8.8 x 10(-6) to 2.0 x 10(-4) M. The detection limit was 9.6 x 10(-9) M. The mechanism of the parallel catalytic wave of diazepam was discussed.

Buffers↗

PubMed2005

Diazepam augments gender differences in cutaneous LD flux response to local cooling.

Cutaneous vasoconstriction in response to local cooling is normally greater in females than in males. Cold induces amplification of alpha2-adrenoceptor affinity for norepinephrine and increases reflex sympathetic thermoregulatory output. Benzodiazepines are drugs with very well-known binding to the central and peripheral benzodiazepine receptors. Besides these effects they decrease sympathetic output and as it was shown in the last decade they act synergistically with alpha-adrenoceptors. In the present study we tested the hypothesis that the benzodiazepine diazepam interacts with an alpha-adrenoceptor mechanism at the level of microcirculation. We measured laser-Doppler blood flux changes provoked by local cooling before and after oral application of a low dose of diazepam (5 mg) in 9 healthy males and in 11 healthy females with regular menstrual cycles. The results of our experiments show that in females there is a significant reduction (ANOVA, p < 0.05) in laser-Doppler flux during the first four minutes of cooling after taking of diazepam. In males, there is no significant difference in the responses to cold before and after an application of diazepam. Our results suggest that diazepam, in addition to its well-known effect on BZ receptors may also interact with alpha2C-adrenoceptors in the vessel wall during local cooling.

Adult↗

PubMed2005

Change in diazepam sensitivity of GABAA currents after LTP induction in neurons of deep cerebellar nuclei.

In deep cerebellar nuclei (DCN) neurons, inhibitory postsynaptic currents (IPSCs) undergo long-term depression (LTD) following a 10-Hz stimulation, and long-term potentiation (LTP) after a 100 Hz stimulation of the inputs. Whole-cell recordings were made from DCN neurons and changes in IPSC sensitivity to diazepam after LTD and LTP investigated. Diazepam enhanced the evoked IPSC amplitude by 45% in controls and after LTD induction. However, after LTP induction, diazepam increased the IPSC by only 16%. Diazepam increased THIP response by 34% in controls, but by only 4% after LTP. These results suggest that during LTP the diazepam sensitive GABAA receptor sub-units undergo changes.

Animals↗

PubMed2004

Effects of diazepam and zolpidem on EEG beta frequencies are behavior-specific in rats.

A pharmacological dissociation of the relation between electroencephalographic (EEG) activity and behavior has been described for the benzodiazepines. While a decrease in high frequency EEG activity is associated with a decrease in arousal in drug-free conditions, sedative benzodiazepines increase beta activity. Non-benzodiazepine GABA(A) receptor modulators can increase beta activity as well. To further study the relationship between rat behavior and EEG under GABA(A) receptor modulation, EEG effects of diazepam (2.5 mg/kg) and zolpidem (2.5 mg/kg) were studied during different behaviors. Both drugs modulate the GABA(A) receptor, albeit that zolpidem shows alpha(1) subunit selectivity while diazepam is non-selective. A detailed analysis of rat open field behavior was made with a distinction of 25 behavioral elements. The EEG was segmented according to each behavioral element and a corresponding power spectrum calculated. Both diazepam and zolpidem increased EEG beta frequencies, characteristic for the benzodiazepines. However, the beta and gamma increase was specific for active behavior and not for inactivity. Interestingly, diazepam and zolpidem seemed to amplify, rather than dissociate, the relation between behavior and the EEG. It is hypothesized that the large increase in beta-3/gamma activity caused by diazepam and zolpidem is a compensatory mechanism that allows for behavioral activation, despite pharmacologically induced sedation.

Animals↗

PubMed2006

Ethological comparison of the effects of a bovine alpha s1-casein tryptic hydrolysate and diazepam on the behaviour of rats in two models of anxiety.

A bovine alpha s1-casein tryptic hydrolysate was previously demonstrated to display an anxiolytic-like activity in the conditioned defensive burying and in the elevated plus-maze models when i.p. injected. The present study assessed the anxiolytic-like effects of this tryptic hydrolysate after an oral administration in rats faced to the same behavioural situations using diazepam as a reference. In a first experiment, the behavioural effects of the hydrolysate in the conditioned defensive burying test were investigated at doses ranging 5-50 mg/kg. The results showed that the minimal dose required to elicit an anxiolytic-like activity is 15 mg/kg. In a second experiment, the alpha s1-casein tryptic hydrolysate (15 mg/kg, p.o.) was demonstrated to display an anxiolytic-like activity similar to diazepam (3 mg/kg, p.o.) in the conditioned defensive burying test and the elevated plus-maze. However, the ethological analysis of behaviour indicated that this hydrolysate has a different activity compared to diazepam. While diazepam induced a disinhibition state in rats, possibly related to the risk-taking behaviour observed after a benzodiazepine ingestion in humans, the tryptic hydrolysate did not display such a side effect. These results suggest that the mechanism of action of the bovine alpha s1-casein tryptic hydrolysate may differ from that of diazepam.

Animals↗

PubMed2006

Protection against soman-induced neuropathology and respiratory failure: a comparison of the efficacy of diazepam and avizafone in guinea pig.

The purpose of this study was to compare the efficacy of diazepam and the pro-diazepam avizafone in preventing the severity of soman-induced pathology in guinea pig. Survival, respiration and seizures of experimental animals were investigated with on-line monitoring of respiratory and EEG parameters. Guinea pigs were pretreated with pyridostigmine (0.1mg/kg i.m.) and 30 min later challenged with 1 or 2 LD50 soman. One minute after intoxication they were treated with atropine (3 or 33.8 mg/kg), pralidoxime chloride (32 mg/kg) and either diazepam (2 mg/kg), avizafone (3.5 mg/kg) or saline solution. The highest dose of atropine (33.8 mg/kg) gave a protective effect in groups treated without anticonvulsants by reducing the severity of clinical signs and death within 24 h but also by decreasing seizure occurrence and brain injuries. When injected at the similar molar dose of 7 micromoles/kg, the protection of anticonvulsants against soman neurotoxicity was higher with the atropine/pralidoxime/avizafone combination than with atropine/pralidoxime/diazepam. Indeed, when atropine was used at the lowest dose, avizafone was found to prevent early mortality and seizures occurrence with better efficacy than diazepam. On the other hand, when added to the therapy, the both anticonvulsants did not prevent the moderate EEG depression (reduction of amplitude by 30-52%) observed under 2 LD50 soman. Moreover, the number of animals suffering from respiratory distress (defined as a decrease of minute ventilation of more than 20% from the baseline value) was enhanced when diazepam or avizafone were used in the therapy. This effect was dependent on the atropine dose and the nature of the anticonvulsant. The beneficial effects of the different therapeutics tested were assessed and compared to the previous data obtained with the same therapies against sarin and from the pharmacokinetics properties of the atropine/diazepam mixture.

Animals↗

PubMed2000

Diazepam-potentiated [3H]phenytoin binding is associated with peripheral-type benzodiazepine receptors and not with voltage-dependent sodium channels.

In the presence of diazepam, [3H]phenytoin binds with high affinity to brain membranes. The present experiments examined whether this high affinity [3H]phenytoin-binding site co-localized with the standard [3H]phenytoin-binding site on the voltage-dependent sodium channel (VDSC). Veratridine, a pharmacological activator of the voltage-dependent sodium channel, that inhibits standard [3H]phenytoin binding, failed to affect the high affinity diazepam-potentiated [3H]phenytoin binding in brain membranes, suggesting that the potentiated binding interaction resides at a site distinct from the voltage-dependent sodium channel. This possibility was confirmed by anion exchange chromatography of digitonin-solubilized rat brain membranes, as diazepam-potentiated high affinity [3H]phenytoin binding eluted in column fractions that were distinct from [3H]saxitoxin-defined voltage-dependent sodium channels. To examine whether diazepam-potentiated [3H]phenytoin binding might be associated with other 'classic' benzodiazepine receptor sites, we tested whether specific ligands for benzodiazepine receptors would either produce or block potentiated [3H]phenytoin binding. Neither agonists, nor antagonists, of the high affinity central-type benzodiazepine receptor affected potentiated [3H]phenytoin binding, suggesting that the high affinity potentiated binding site is not likely associated with central benzodiazepine receptors. Peripheral-type benzodiazepine receptor agonists, however, did potentiate [3H]phenytoin binding, and a specific receptor antagonist (PK11195) attenuated the potentiation seen with diazepam. Overall, these data illustrate that [3H]phenytoin interacts with a novel site in brain membranes that is distinct from the voltage-dependent sodium channel and is allosterically revealed by peripheral-type, but not central-type, benzodiazepine receptor agonists.

Animals↗

PubMed1997

Diazepam-sensitive GABA(A) receptors in the NTS participate in cardiovascular control.

The present study employed neuropharmacological and receptor binding protocols to determine if diazepam-sensitive (DS) gamma-aminobutyric acid-A (GABA(A)) receptors in the nucleus tractus solitarius (NTS) participate in autonomic regulation of cardiovascular function. The first set of protocols was designed to determine if GABA(A) receptors in the NTS were functionally modulated by the benzodiazepine agonist, diazepam. Mean arterial pressure and heart rate responses to microinjection of GABAergic substances into the NTS were examined in urethane-anesthetized rats. Microinjection of the GABA(A) agonist isoguvacine into the NTS increased mean arterial pressure and heart rate, and these effects were blocked by the GABA(A) receptor antagonist, bicuculline. Preadministration of diazepam into the NTS potentiated the pressor actions of isoguvacine and had variable effects on heart rate changes. Flumazenil, a benzodiazepine antagonist, blocked the diazepam-induced potentiation of the pressor response to isoguvacine. The second protocol employed receptor autoradiography to examine the presence of DS and diazepam-insensitive (DI) GABA(A) receptors in the NTS. Autoradiography confirmed that DS GABA(A) receptors were present in the NTS; however, no measurable levels of DI GABA(A) receptors were detected. We conclude that GABA(A)-mediated integration of central autonomic control in the NTS is mediated solely by DS GABA(A) receptors.

Affinity Labels↗

PubMed1999

Dizocilpine does not prevent the development of tolerance to the anxiolytic effects of diazepam in rats.

The non-competitive NMDA receptor antagonist, dizocilpine (0.25 mg/kg), has previously been shown to block the development of tolerance to the sedative effects of diazepam (2 mg/kg). Since there is considerable evidence that different mechanisms underlie the development of tolerance to the sedative and anxiolytic effects of diazepam, the present experiment examined whether dizocilpine would block the development of tolerance to diazepam's anxiolytic effects. Rats tested after an acute dose of diazepam (2 mg/kg) showed an anxiolytic effect, measured by an increase in the time spent in social interaction, whereas those tested after 21 days of treatment had scores equal to the control group. This development of tolerance was not blocked by concomitant administration of dizocilpine (0.25 mg/kg). Thus, these results provide further evidence that the mechanism underlying tolerance to the anxiolytic effects of diazepam is different from that underlying tolerance to the sedative effects.

Animals↗