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PubMedDate not supplied

Effects of subacutely administered saiboku-to, an oriental herbal medicine, on pharmacodynamics and pharmacokinetics of diazepam in rodents.

Subacute treatment with saiboku-to (2000 mg/kg, p.o., once a day) for 7 days induced an anxiolytic-like effect in rats. It did not, however, produce any other effects, such as sedative and hypnotic effects, anticonvulsive and muscle relaxant effects except for anxiolytic effect observed in diazepam-injected rats or mice. Diazepam (1.0 mg/kg, s.c.) induced anxiolytic-like effect was enhanced in saiboku-to treated rats as an additional effect of that induced by saiboku-to. To elucidate whether the enhancement of the anxiolytic-like effect following combined administration of diazepam and saiboku-to is due to the inhibition of hepatic drug-metabolizing enzymes, the pharmacokinetics of diazepam were further investigated in saiboku-to treated rats. The pharmacokinetic studies clearly demonstrated that subacute treatment with saiboku-to did not affect plasma concentration and protein binding rate of diazepam, and the activities of hepatic drug-metabolizing enzymes related to diazepam metabolism. These results, taken together, suggest that the enhancement of diazepam-induced anxiolytic-like effect observed in saiboku-to-treated rats is not due to an inhibition of diazepam metabolism.

Animals↗
PubMed1997

Evidence that the median raphé nucleus--dorsal hippocampal pathway mediates diazepam withdrawal-induced anxiety.

On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphé nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then tested after 24 h withdrawal in the social interaction test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K(+)-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to test these animals in the social interaction test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and tested in the low light familiar condition of the social interaction test. 8-OH DPAT (50-200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.

Animals↗
PubMed1999

Dissociating neuromodulatory effects of diazepam on episodic memory encoding and executive function.

RATIONALE: Diazepam and other benzodiazepines impair episodic memory encoding. Deficits in tests of executive function are also reported. In this study, we ask whether the latter effects are secondary to mnemonic impairment, or reflect specific and distinct effects of benzodiazepines on executive function. OBJECTIVES: Using positron emission tomography in healthy human volunteers, we examined similarities in the neuroanatomical correlates of the effect of diazepam on performance of executive compared to episodic memory tasks. Close similarities are proposed to reflect commonalities in the functional effects of the drug. Conversely, any evidence of task-specific regional changes in activity is proposed to reflect distinct functional effects of DZP on the two tasks. METHODS: Twelve volunteers received placebo or 10 mg diazepam in a between-subjects design. During scanning, subjects performed one of four experimental conditions, corresponding to a 2x2 factorial design, with memory encoding and executive function (on-line ordering of stimuli) as the two factors. Drug- or task-induced changes in brain activation indexed the neuroanatomical correlates of each condition. RESULTS: Averaged across all conditions, and compared to placebo, diazepam decreased activity bilaterally in prefrontal and temporal cortices. Within this network of deactivation, left dorsal prefrontal cortex activity was attenuated by diazepam during memory encoding, while left frontal opercular activity was attenuated during ordering. CONCLUSION: This neuroanatomical dissociation reflects distinct functional effects of diazepam on encoding versus ordering tasks. Therefore, the effects of diazepam on ordering tasks are not simply secondary to diazepam effects on episodic memory, but reflect real and distinct effects of the drug on executive function.

Adult↗
PubMed2000

Diazepam-like effects of a fish protein hydrolysate (Gabolysat PC60) on stress responsiveness of the rat pituitary-adrenal system and sympathoadrenal activity.

RATIONALE: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. OBJECTIVE: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. METHODS: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1,200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. RESULTS: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1,200 mg/kg). Both diazepam and PC60 (1,200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. CONCLUSIONS: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.

Administration, Inhalation↗
PubMed1984

The benzodiazepine agonist diazepam inhibits basal and secretagogue-stimulated prolactin release in vitro.

Benzodiazepines reduce basal and stimulated rat prolactin (PRL) serum levels in vivo. We investigated whether the inhibition of PRL secretion by the benzodiazepine receptor agonist, diazepam, occurs directly at the pituitary. At nanomolar concentrations diazepam did not affect PRL secretion, whereas at micromolar concentrations, diazepam dose-dependently inhibited basal and secretagogue-stimulated PRL release from hemipituitary glands and from primary cultures of rat anterior pituitary cells. The inhibitory effect of the highest concentration of diazepam (100 microM) was abolished when the pituitary tissue was incubated with the benzodiazepine receptor antagonist Ro 15-1788. Although nanomolar concentrations of diazepam alone did not affect PRL release, they did enhance the PRL inhibitory effect of muscimol, a gamma-amino butyric acid (GABA) receptor agonist. Neither diazepam nor muscimol affected cellular adenosine 3',5'-monophosphate (cAMP) content. Since these effects do not appear to occur through an inhibition of the cAMP generating system, diazepam may inhibit PRL release via a cAMP-independent pathway. We suggest that diazepam inhibits PRL secretion either by enhancing the GABAergic inhibition of PRL release, or by inhibiting, at micromolar concentrations, a benzodiazepine-sensitive Ca2+-calmodulin dependent protein kinase.

Animals↗
PubMed1995

Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation.

OBJECTIVE: To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status. STUDY DESIGN: Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam. RESULTS: Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05). CONCLUSION: The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1992

Effects of drugs on behavior before and during chronic diazepam administration.

The effects of diazepam, pentobarbital, and phencyclidine (PCP) were studied on punished and unpunished responding maintained by fixed-interval schedules before and during chronic administration of diazepam. Before chronic diazepam administration, increasing doses of diazepam and PCP increased and then decreased rates of both punished and unpunished responding. Increases in punished responding were larger than increases in unpunished responding. Pentobarbital only increased punished responding, while higher doses decreased both rates of punished and unpunished responding. During chronic diazepam administration, rates of punished and unpunished responding showed further increases with all three drugs and the dose-effect curves also shifted to the right. Analysis of local rates of responding within fixed-interval components suggested that increases in low rates early in the interval were responsible for the rate increases produced by these drugs before chronic diazepam administration. During chronic diazepam administration low rates early in the interval showed greater increases after all three drugs and their ability to produce rate-increasing effects extended further into the interval. The similar effects of these drugs before and during chronic diazepam administration suggests a similar mechanism despite the widely recognized differences in their interaction with receptors. This common mechanism may relate to rate-increasing effects more than to specific effects on punished responding.

Animals↗
PubMed1995

Stereospecific transduction of behavioral effects via diazepam-insensitive GABAA receptors.

Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABAA receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-(S)-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c] [1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABAA receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity (Ki > 1 microM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-met hyl-6H- imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABAA receptors, had high diazepam-insensitive receptor affinity (Ki = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.

Animals↗
PubMed1986

Marked variation in diazepam sensitivity in Swiss albino mice.

Using the righting reflex as the critical level, sleep was measured in Swiss albino mice at a dose of 35 mg/kg diazepam, i.p. Sleep times varied markedly from zero to 120 min with a mean +/- s.d. of 44 +/- 37 (N = 202). The distribution is skewed to the left with a coefficient of skewness of 0.33 +/- 0.17. The sleep times of the two sexes, when analyzed separately, showed similar range, mean and s.d., except that the distribution tended to be more clearly bimodal in males than in females. These animals also exhibited marked variations in their response to either ethanol (4 g/kg) or pentobarbital (45 mg/kg). The diazepam sleep time failed to correlate with the ethanol sleep time. Significant correlation, however, was obtained between diazepam and pentobarbital sleep times. On further analysis with least-squares fit to a straight line, the data yielded a line with a slope of 0.16; thus despite the correlation reaching a significant level, there is no significant difference in the pentobarbital sleep times between mice that have the longest or the shortest diazepam sleep times. By monitoring the plasma and brain levels of diazepam and N-desmethyldiazepam in mice at awakening, it was found that the variations in sleep time cannot be explained by individual differences in drug disposition. The phenomenon is discussed in terms of individual variations in diazepam sensitivity and the possibility of development of tolerance to diazepam almost immediately after diazepam administration.

Animals↗
PubMed1991

A comparison of the physical dependence inducing properties of flunitrazepam and diazepam.

Dogs dosed chronically (4-7 weeks) with oral flunitrazepam (7.6 mg/kg/day) or diazepam (24-36 mg/kg/day) administered in 4 equally divided doses had dose-related flumazenil precipitated benzodiazepine abstinence scale scores (BPAS) of comparable intensities despite the fact that plasma levels of flunitrazepam and its metabolites were much lower than nordiazepam levels in the diazepam-dependent dog. Both groups of dependent dogs had clonic and tonic-clonic seizures after oral and IV flumazenil. Precipitated abstinence signs persisted longer in the diazepam than in the flunitrazepam-dependent dogs. Differences in the pharmacokinetics of the drugs of dependence, their metabolites, and their interactions at receptor sites offer a partial explanation for the high level of dependence seen in the flunitrazepam dog. The finding that the estimated plasma free concentration of flunitrazepam and its metabolites is equal to or greater than that of diazepam and its metabolites together with the fact that flunitrazepam has a higher affinity for the benzodiazepine receptor than either diazepam, nordiazepam or oxazepam can explain why the intensity of the precipitated abstinence syndrome is comparable in flunitrazepam- and diazepam-dependent dogs. Although the flumazenil-induced precipitated abstinence syndromes observed in flunitrazepam- and diazepam-dependent dogs differed qualitatively they did not differ quantitatively. It is therefore concluded from these data that the doses of flunitrazepam and diazepam, chosen for producing comparable degrees of weight loss during dose escalation, did not differ in the degree of physical dependence that they produced in the dog.

Animals↗
PubMed1995

The effects of long-term, low-dose diazepam treatment on the guinea pig righting reflex and medial vestibular nucleus neuronal activity.

Guinea pigs received a 2 mg/kg IP injection of diazepam, or an equivalent volume of vehicle, daily for 28-60 days. To determine whether tolerance developed to the ataxic effects of diazepam on the righting reflex, daily righting reflex latency (RRL) measurements were made before and 20, 30, and 40 min following the diazepam or vehicle injection for 28 days. Analyses of the RRLs for individual animals indicated that a significant decrease in RRL over time (indicating tolerance) occurred in only one out of nine animals receiving diazepam and in none of the vehicle animals. Medial vestibular nucleus (MVN) neurons in brain stem slices from animals receiving chronic diazepam treatment had a significantly higher average firing rate than those from vehicle controls. These results suggest that: a) long-term treatment with single 2 mg/kg daily IP injections of diazepam does not result in tolerance to diazepam's ataxic effects on the righting reflex in the majority of animals; b) this form of diazepam treatment may, nonetheless, induce a hyperactivity of brain stem MVN neurons that may be consistent with the occurrence of a withdrawal syndrome.

Animals↗
PubMed2004

[Use of diazepam in the treatment of opioid neonatal abstinence syndrome].

INTRODUCTION: The fetal opiate exposure presents many risks for the newborn. One of the most important is the neonatal abstinence syndrome that associates neurological and digestive signs. In some cases the vital prognosis can be involved. The evaluation of the syndrome's severity is based on certificated scales. The mortality has been reduced by the improved management of these neonates. Diamorphine, phenobarbital, chlorpromazine and diazepam are the most currently used. However, there is no consensus on the treatment. The data concerning the treatment are controversial, especially for the use of diazepam. The aim of our study was to describe the effects of diazepam obtained in three different centers and to compare our results to those of the literature. POPULATION AND METHODS: Twenty-three neonates were included. They were all hospitalized for abstinence syndrome and treated by diazepam. The Finnegan scale was used to evaluate the symptom's severity and the effects of the diazepam. The principal evaluation criteria were the duration of treatment and hospitalization, the timing in recovery of birth weight and the percentage of birth weight loss. RESULTS: The average treatment duration was 7 days, the average hospitalization duration was 18 days, the birth weight was recovered at 10 days of life and the percentage of loss of birth weight was 6.5%. Diazepam treatment failed in only one case. No case of intense dehydration occurred. CONCLUSION: Due to the retrospective design of the study, the diazepam could not be compared to other drugs. Nevertheless, it argues against the "anti-diazepam" attitude. A controlled randomised prospective study is needed to evaluated the optimal therapeutic strategy.

Adult↗
PubMed2006

The systemic application of diazepam facilitates the reacquisition of a well-balanced vestibular function in a unilateral vestibular re-input model with intracochlear tetrodotoxin infusion using an osmotic pump.

Diazepam is a popular medicine used in the treatment of acute vertigo. In the past, many studies investigating the effect of diazepam in peripheral vestibular destruction have been reported. However, no previous study has yet investigated the effect of diazepam on a model with a transient and reversible vestibular function similar to recurrent vertigo as seen in Meniere's disease. We thus made a peripheral vestibular re-input model by the unilateral intracochlear administration of tetrodotoxin (TTX) using an osmotic pump and then examined the influence of diazepam on the vestibular system in this model. Hartley white guinea pigs were intracochlearly administered with TTX on the right side for 3 days by an osmotic pump. Animals were divided into three groups, TTX alone (control group (n = 7)), TTX and an intraperitoneal diazepam injection once a day for 3 days (diazepam group (n = 6)) and vehicle injection (vehicle group (n = 6)). A caloric response and vestibuloocular reflex (VOR) were observed at 7 and 14 days after completing 3 days of TTX administration. Seven days after vestibular re-input, a directional preponderance of the nystagmus (DP) to the TTX-treated side was observed in the control and vehicle groups on VOR examination. DP was not observed in the diazepam group on any examined day. The R/L time ratio of caloric response showed no statistical difference between three groups on any examined day. These results suggest that diazepam may thus be useful for patients in an acute stage of peripheral vestibular vertigo by decreasing their vertiginous symptoms.

Anesthetics, Local↗
PubMed2003

Effects of acute and long-term diazepam administrations on neutrophil activity: a flow cytometric study.

This study analyzed the effects of acute and long-term diazepam treatments on rat peripheral blood neutrophil activity and cortisol serum levels. Rats were acutely and long-term (21 days, once daily) treated with diazepam (10 mg/kg) or its vehicle (1.0 ml/kg). Blood was collected 1 h after treatments for flow cytometric analysis of neutrophil oxidative burst and phagocytosis. Corticosterone and diazepam concentrations were also determined. Results showed that: (1) both diazepam treatments increased lipopolysaccharide (LPS) and phorbol myristate acetate (PMA)-induced neutrophil oxidative burst; (2) the increase in oxidative burst after Staphylococcus aureus induction in acutely treated animals was higher than that observed after long-term treatment; (3) phagocytosis is increased by acute diazepam treatment and decreased by a long-term regimen; (4) acute, but not long-term, diazepam treatment increased corticosterone levels; (5) diazepam plasmatic levels after acute and long-term treatments were not different. These results indicate the development of tolerance to diazepam effects on corticosterone serum levels but not on neutrophil activity.

Animals↗
PubMed2005

Imidazenil: an antagonist of the sedative but not the anticonvulsant action of diazepam.

Flumazenil (FLU), a specific benzodiazepine (BZ) receptor antagonist has been used in the treatment of acute BZ intoxication or the alleviation of BZ-induced withdrawal syndrome on the basis of its weak partial agonist action at GABA(A) receptors. However, given to patients, FLU can worsen diazepam-induced withdrawal syndrome by lowering seizure threshold. We therefore investigated whether imidazenil, a selective positive allosteric modulator of GABA action at GABA(A) receptors containing alpha5 subunit, can antagonize diazepam-induced sedative action and suppression of locomotor activity without affecting diazepam anti-bicuculline action. We report here that while FLU (16.5 micromol/kg) showed no effect on locomotor activity and bicuculline-induced convulsion, it completely antagonized diazepam (10.5 micromol/kg) anti-bicuculline action and the suppression of locomotor activity. However, imidazenil (0.76 micromol/kg) elicited anti-bicuculline action and was dose-dependently antagonized by FLU (16.5 and 33 micromol/kg). Furthermore, imidazenil showed no effect on path length traveled but slightly decreased (40%) horizontal activity when compared to diazepam (85%), and maintained the anti-bicuculline action of diazepam to a threshold level similar to that observed with diazepam. Whereas cross-tolerance between BZs has been reported in animals and humans, we previously reported the absence of cross-tolerance between imidazenil and diazepam. Thus, we suggest that imidazenil might be more effective than FLU at alleviating the withdrawal syndrome associated with long-term BZ administration.

Animals↗
PubMed2005

Endogenous opioids are necessary for benzodiazepine palatability enhancement: naltrexone blocks diazepam-induced increase of sucrose-'liking'.

Opioid agonists and benzodiazepine agonists each increase food intake. Both also increase hedonic 'liking' reactions to sweet tastes in rats. Do opioids and benzodiazepines share overlapping mechanisms of hedonic impact? Or are benzodiazepine and opioid effects on hedonic impact mediated by independent mechanisms? The present study examined whether blockade of opioid receptors prevents benzodiazepine-induced enhancement of taste palatability, as assessed by the affective taste reactivity test. Rats were implanted with oral cannulae, and prior to an oral infusion of bittersweet quinine-sucrose solution, all received i.p. injections of either vehicle, or diazepam alone (5 mg/kg diazepam+0 mg/kg naltrexone), naltrexone alone (1 mg/kg naltrexone+0 mg diazepam), or both diazepam plus naltrexone (5 mg/kg diazepam+1mg/kg naltrexone). Videotaped hedonic ('liking') and aversive ('disliking') orofacial reactions elicited by sucrose/quinine taste were compared across drug conditions. Diazepam administration alone more than doubled hedonic 'liking' reactions to the bittersweet taste, while reducing 'disliking' in half, compared to vehicle levels. Naltrexone by itself had little effect on taste-elicited affective reactions, and only marginally increased aversive gapes. However, naltrexone completely blocked diazepam's enhancement of positive hedonic 'liking' reactions, and naltrexone similarly disrupted diazepam-reduction of aversive 'disliking' taste reactions. These results indicate that endogenous opioid neurotransmission may be crucial to benzodiazepine enhancement of hedonic 'liking' for natural taste reward.

Analysis of Variance↗
PubMed1976

Therapeutic implications of diazepam in patients with elevated left ventricular filling pressure.

Diazepam (0.1 mg. per kilogram) was given intravenously to 12 patients with hemodynamic left ventricular failure at the time of cardiac catheterization. Anxiety was effectively relieved in 10 patients. Systemic and coronary hemodynamic parameters were assessed before and 5 and 15 minutes after diazepam. Heart rate, cardiac index, and left ventricular stroke-work index did not change significantly. Mean aortic pressure decreased in all patients (average of 10 mm. Hg) and left ventricular end-diastolic pressure (LVEDP) decreased from a mean +/- S.E.M. of 24.3 +/- 3 mm. Hg at rest to 16 +/- 2.1 at 5 minutes (p less than 0.001) and 15.8 +/- 2.1 at 5 minutes (p less than 0.002). Left ventricular angiography performed 30 minutes after diazepam did not increase LVEDP above the pre-diazepam control value. Systolic ejection period and tension-time index also decreased significantly after diazepam. Coronary hemodynamics and myocardial metabolism were unaltered by diazepam. The fall in LVEDP induced by diazepam is probably secondary to a decrease in arterial pressure (afterload) possibly associated with a decrease in venous return (preload). Our data therefore suggest that diazepam exerts a beneficial action on depressed left ventricular function and, thus, may be a sedative agent of choice in patients with myocardial infarction and heart failure.

Anxiety↗
PubMed1999

Diazepam-induced neuroprotection: dissociating the effects of hypothermia following global ischemia.

Global cerebral ischemia produces hippocampal CA1 neuronal loss which in turn leads to deficits in memory related tasks. Previous studies have shown that the benzodiazepine diazepam is effective at attenuating this cell death and the related behavioural impairments. However these studies have been confounded by diazepam-induced hypothermia. In this study we sought to determine the neuroprotective efficacy of diazepam in the absence of hypothermia. Diazepam (10 mg/kg) was administered to two groups of gerbils at 30 and 90 min following a 5-min ischemic insult. In one group the brain temperature was monitored for 24 h post-ischemically but not regulated. In the second group, post-ischemic brain temperature was maintained at 36.5 degrees C to counteract the hypothermia produced by diazepam. Both behaviour (open field performance) and CA1 cell counts from these groups were compared to those from sham/normal, no drug ischemic and vehicle ischemic groups at 10 days survival. In animals treated with diazepam without temperature regulation, there was significant histological and behavioural protection at 10 days compared to untreated ischemic animals. Preventing hypothermia in diazepam-treated animals resulted in a decrease in the number of cells surviving (from 41.2 to 31.6% of sham) and abolished behavioural protection. Diazepam appears to have limited ability to attenuate neuronal loss and its neuroprotective efficacy is augmented by the concurrent hypothermic actions of the drug itself.

Animals↗