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PubMed1999

Increased expression of peripheral benzodiazepine receptors and diazepam binding inhibitor in human tumors sited in the liver.

The peripheral benzodiazepine receptor system triggers intracellular metabolic events and has been associated with cell proliferation. Its endogenous ligand, the diazepam binding inhibitor, contributes to steroidogenesis by promoting cholesterol delivery to the inner mitochondrial membrane. The present study was undertaken to verify whether this system is altered in tumors sited in the liver. Peripheral benzodiazepine receptors and diazepam binding inhibitor were studied using immunocytochemistry and in situ hybridization in 9 human tumors sited in the liver, in liver hyperplasia, cirrhotic nodular regeneration, intestinal adenocarcinoma and in surrounding non-tumoral tissue. Immunocytochemical staining and in situ hybridization demonstrated that peripheral benzodiazepine receptors and diazepam binding inhibitor were more prominently expressed in neoplastic cells than in non-tumoral tissue. They were present in the same cells, suggesting that diazepam binding inhibitor may act in an intracrine manner in these cells. Higher peripheral benzodiazepine receptors and diazepam binding inhibitor expression in tumor cells suggest an implication of this system in the metabolism of neoplastic cells. Furthermore the evaluation of peripheral benzodiazepine receptor and diazepam binding inhibitor expression might be useful in evaluating malignancy and in diagnostic approaches of tumors in liver tissue.

Aged↗
PubMed2000

Gender, estrous cycle, ovariectomy, and ovarian hormones influence the effects of diazepam on avoidance conditioning in rats.

This study examines whether the hormonal condition of the rat modifies the effects of diazepam (0.25 and 1.0 mg/kg) on avoidance conditioning and other behavioral responses. Acquisition of a conditioning avoidance response (CAR) and spontaneous motor behaviors were assessed in intact male, in intact diestrous and estrous females, and in ovariectomized (OVX) rats injected with estradiol (2 microg/rat, SC) or progesterone (5 mg/rat, SC). A higher dose (1.0 mg/kg) of diazepam significantly impaired the acquisition of CARs in diestrous, OVX, OVX + progesterone, and male rats. Conversely, both doses of diazepam significantly improved the acquisition of CAR in estrous rats and in OVX rats injected with estradiol. These effects on conditioning avoidance were not accompanied with equivalent changes in spontaneous motor behaviors. Motor activity and grooming behavior decreased in all experimental groups after administration of 1.0 mg/kg of diazepam. On the contrary, diazepam 0.25 mg/kg increased motor activity in estrous, OVX + estradiol, and OVX + progesterone rats after, whereas grooming behavior was not affected in any group. These findings suggest a physiological influence of ovarian steroid hormones in modifying the benzodiazepine effects on conditioning avoidance and motor activity. The results are discussed considering that ovarian steroids may interact with diazepam on the GABA(A)/benzodiazapine/chloride ionophore complex, modifying the coupling between benzodiazepine sites and GABA(A) receptors.

Animals↗
PubMed1984

Tolerance to the depressant effects of diazepam in the drug discrimination paradigm.

Seven groups of rats (n = 35) were run in operant drug experiments. All groups were trained on a Fixed Ratio 10 schedule to discriminate diazepam from saline. Two groups (n = 7, n = 6), after extensive drug discrimination training (doses of 2.0 and 3.0 mg/kg diazepam), were submitted to generalization experiments with various doses of the training drug. Two additional groups, (n = 6, n = 8) in the initial phase of drug discrimination, were trained on intermediate and high doses of diazepam (i.e., 5.0 and 10.0 mg/kg). The development of tolerance to the depressant effects of diazepam for these two groups was compared to the low dose sophisticated rats. Of the above-mentioned groups, two groups were given tests after a waiting period in drug discrimination training. In this test the two groups were compared to an additional group (n = 8) in its initial phases of drug discrimination training. The results show that a large number of low doses (i.e., doses below 3.0 mg/kg) is not able to induce any tolerance to the depressant effects of diazepam in this particular paradigm. Intermediate doses of diazepam (i.e., 3.0 mg/kg), administered in a large number, induced some tolerance to the depressant effects, while another intermediate dose (5.0 mg/kg) and a high dose (10.0 mg/kg) rapidly induced a significant tolerance. Once developed, the tolerance persisted for 51 days.

Analysis of Variance↗
PubMed1997

Effect of diazepam and A beta-carboline on open-field and T-maze behaviors in 2-day-old chicks.

The effects of diazepam and the beta-carboline FG 7142 in chicks were examined on several behavioral measures in open-field and T-maze tasks. In the open field, only the higher doses of diazepam affected behavior, suggesting a sedative-like effect, while FG 7142 influenced behavior as would a fear-inducing manipulation. After a low dose of either drug was injected, testing in a T-maze showed that diazepam improved and FG 7142 impaired the escape performance from the isolation chamber, without affecting the time spent in the T-corridor. In three groups of chicks selected on the basis of their first escape performance, only lower performance chicks were affected by an anxiolytic dose of diazepam. T-maze results suggest that: (a) T-maze is more sensitive than open-field test to behavior changes induced by anxiolytic doses of diazepam; (b) isolation chamber behavior could be an index of general emotionality in young chicks; (c) diazepam and FG 7142 do not modify the social motivation to escape the maze; (d) higher performance chicks present an escape behavior of a less anxious type than lower performance chicks. The results suggest that the GABAergic system is involved in the behavioral expression of fear and anxiety in young chicks.

Animals↗
PubMed1997

Comparison of triazolam, diazepam, and placebo as outpatient oral premedication for endodontic patients.

Triazolam and diazepam were compared as oral antianxiety agents in a randomized double-blind, placebo-controlled clinical study of 79 endodontic patients with elevated anxiety regarding endodontic treatment. Patients who scored > or = 10 on the Corah Dental Anxiety Survey received oral formulations of triazolam (0.25 mg), diazepam (5 mg), or placebo. Before, during, and after the endodontic procedure, patients completed psychomotor tests and anxiety scales, and were evaluated for 24-h postoperative recall. In comparison with diazepam and placebo, triazolam was significantly better for decreased anxiety (p < 0.05), impaired cognitive function (p < 0.05), patients' rating of drug effectiveness (p < 0.05), and amnesia to clinical events (p < 0.02) and pictures (p < 0.03). Diazepam showed similar trends compared with placebo, but to a lesser degree. Diazepam also had a much longer recovery period. No adverse effects were noted with either drug. These findings suggest that orally administered triazolam (0.25 mg) is a safe and more effective anxiolytic agent than diazepam (5.0 mg) for endodontic patients.

Adjuvants, Anesthesia↗
PubMed1999

Effects of prenatal diazepam treatment on Mycobacterium bovis-induced infection in hamsters.

In utero exposure of rats to low dosages of diazepam has been found to result in depression of cellular and humoral immune responses during adulthood, with marked changes in macrophage spreading and phagocytosis. The present experiment was undertaken to investigate the resistance of adult hamsters to Mycobacterium bovis after prenatal exposure to diazepam. Time-pregnant hamsters were exposed to diazepam (1.0 or 1.5 mg kg(-1) day(-1) subcutaneously) or vehicle from gestational day 9 to 15. A total of 36 different litters (12 of them control and 12 for each experimental group) born after a 16/17-day gestation were used. One male from each litter was infected twice with identical inoculum concentrations of M. bovis at 75 and 107 days of age. This infection model involves the participation of macrophages and T and B cell populations. The animals prenatally exposed to the higher (1.5 mg/kg) dose of diazepam exhibited: (1) increased weight loss, (2) increased mortality, (3) increased granuloma areas measured in the liver, lung and spleen, (4) increased spleen weight, and (5) increased scores of M. bovis colony forming units (CFU) isolated from liver, lung and spleen. These effects were dose-dependent, and were not detected or were less severe in animals treated with the lower (1.0 mg/kg) dose of diazepam as well as in those of the control group. The present data demonstrate an impaired defence against M. bovis in adult hamsters after in utero exposure to a dosage of 1.5 mg/kg of diazepam.

Animals↗
PubMed1998

Small platform stress attenuates the anxiogenic effect of diazepam withdrawal in the plus-maze test.

The effect of stress on the behavioural changes caused by diazepam withdrawal was studied in mice. Diazepam (2.5 mg/kg) or vehicle was injected intraperitoneally twice a day for 2 weeks. When the last vehicle or diazepam injection had been administered to the mice, 12 h later, the mice were subjected to small platform stress exposure or left in their home cages. Small platform stress was induced by placing mice on small platforms (3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several factors of stress like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. The plus-maze test was carried out with stressed mice as well as with mice not subjected to stress. Small platform stress induced an anxiolytic effect and diazepam withdrawal--an anxiogenic effect in the plus-maze test. Small platform stress also attenuated the anxiogenic effect of diazepam withdrawal. On the basis of this data it was proposed that small platform stress counteracts the anxiogenic effect of diazepam withdrawal in the plus-maze test. It was also proposed that the effect of stress on the signs of benzodiazepine withdrawal depends on the characteristics and duration of stress.

Animals↗
PubMed2000

Induction of NGFI-B mRNA following contextual fear conditioning and its blockade by diazepam.

Expression of the immediate-early gene, NGFI-B (nerve growth factor inducible gene B), was examined in the amygdala, hippocampus, and neocortex following contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Only the delayed-shock group displayed a fear response (freezing) in the post-shock period and in a retention test 24 h after fear conditioning. Expression of NGFI-B mRNA was increased in the dorsolateral part of the lateral nucleus of the amygdala (LaDL) and the neocortex 30 min following conditioning in the delayed-shock group compared to the other three groups. In addition, following a retention test conducted 24 h after fear conditioning, NGFI-B mRNA expression was increased in the neocortex of the delayed-shock group compared to the handled group. In a subsequent experiment, the effects of pretreatment with the anxiolytic drug, diazepam, on fear conditioning and the concomitant increases in NGFI-B mRNA were investigated. Rats administered a 2.5 mg/kg, i.p. dose of diazepam before fear conditioning did not acquire contextual fear as demonstrated by a lack of freezing in a retention test. Although diazepam blocked fear conditioning while the 40% propylene glycol, 10% ethanol vehicle solution did not, both diazepam and the vehicle reduced the conditioning-induced increase in NGFI-B expression in the LaDL. In contrast, the fear-conditioning-induced NGFI-B increase in the neocortex was blocked by diazepam, but not by the vehicle. The data suggest that the transcriptional factor NGFI-B in the LaDL and neocortex may play a functional role in learning and memory of contextual fear, but blocking the increase in NGFI-B expression in the LaDL is not essential for diazepam to interfere with fear conditioning.

Amygdala↗
PubMed1991

Diazepam and intubation in emergency treatment of seizures in children.

STUDY OBJECTIVES: This study was undertaken to determine the incidence of endotracheal intubation after the use of diazepam compared with phenobarbital or phenytoin in emergency treatment of seizures in children. DESIGN: The records of all children (98) were reviewed in a case-control fashion. A logistic regression model was used to determine whether there was an association between diazepam administration and intubation, adjusting for all other covariates (age, weight, convulsion time before first anticonvulsant was given, response latency, diagnosis, and therapy). SETTING: All children were treated in an emergency department and then transported to a tertiary pediatric center by a pediatric transport team. TYPE OF PARTICIPANTS: All patients were children, with a median age of 2.7 years (range 0.17 to 15.3 years). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Only the use of diazepam was found to be significantly associated with intubation after adjusting for all other covariates (adjusted odds ratio, 49.4; P less than .001). In the comparison of diazepam versus phenobarbital or phenytoin used as the first anticonvulsant, median response latency did not differ (27.0 vs 32.5 minutes, P greater than .83). CONCLUSION: A significant association was found between diazepam use and intubation. Response latency was not shorter when diazepam was used as the initial anticonvulsant compared with phenobarbital or phenytoin.

Adolescent↗
PubMed1991

Comparison of various physiologic and psychomotor parameters in patients sedated with intravenous lorazepam, diazepam, or midazolam during oral surgery.

Intravenously administered lorazepam (0.05 mg/kg), diazepam (0.25 mg/kg), and midazolam (0.1 mg/kg) were compared for sedation during oral surgery under local anesthesia. Sixty patients were randomly allocated into three groups in this double-blind, parallel study. The results from this trial show that all three drugs provide satisfactory sedation. Average mean arterial pressures, however, decreased significantly with midazolam and diazepam. Statistically significantly higher heart rates during the entire procedure were also found for lorazepam when compared with diazepam and midazolam. At the postblock stage, the midazolam group had respiratory rates that were significantly higher than those of the other two drug groups. Patients in the diazepam and midazolam groups took significantly longer to complete the pegboard test at the preblock stage than those in the lorzepam group. At 1, 1.5, and 2 hours after arrival in the recovery room, an inversion of groups took place, with the lorazepam group taking significantly longer for their tests than the other two groups. Significantly more improvement in anxiety levels was found at 10 minutes postdrug for the patients who had received diazepam and this tended to remain so on arrival in the recovery room. When compared with the other two groups, significantly more patients in the lorazepam group reported giddiness/dizziness and significantly more in the diazepam group reported pain on injection.

Adolescent↗
PubMed2003

Comparative efficacy of diazepam and avizafone against sarin-induced neuropathology and respiratory failure in guinea pigs: influence of atropine dose.

This investigation compared the efficacy of diazepam and the water-soluble prodiazepam-avizafone-in sarin poisoning therapy. Guinea pigs, pretreated with pyridostigmine 0.1 mg/kg, were intoxicated with 4LD(50) of sarin (s.c. route) and 1 min after intoxication treated by intramuscular injection of atropine (3 or 33.8 mg/kg), pralidoxime (32 mg/kg) and either diazepam (2 mg/kg) or avizafone (3.5 mg/kg). EEG and pneumo-physiological parameters were simultaneously recorded. When atropine was administered at a dose of 3 mg/kg, seizures were observed in 87.5% of the cases; if an anticonvulsant was added (diazepam (2 mg/kg) or avizafone (3.5 mg/kg)), seizure was prevented but respiratory disorders were observed. At 33.8 mg/kg, atropine markedly increased the seizure threshold and prevented early respiratory distress induced by sarin. When diazepam was administered together with atropine, seizures were not observed but 62.5% of the animals displayed respiratory difficulties. These symptoms were not observed when using avizafone. The pharmacokinetic data showed marked variation of the plasma levels of atropine and diazepam in different antidote combination groups, where groups receiving diazepam exhibited the lowest concentration of atropine in plasma. Taken together, the results indicate that avizafone is suitable in therapy against sarin when an anticonvulsant is judged necessary.

Animals↗
PubMed1997

Event-related potentials in a passive and active auditory condition: effects of diazepam and buspirone on slow wave positivity.

The effects of single, oral doses of diazepam (10 mg), buspirone (10 mg) and placebo on auditory event-related potentials were assessed in healthy volunteers. Subjects received two series of auditory stimuli: a series of identical stimuli presented in a neutral, passive condition and a series of identical standard tones (P = 0.8), but now intermixed with target tones (P = 0.2), in an active, oddball condition. The analysis focused on the average value of the potential in two different phases, from 250 till 574 ms post-stimulus (including P300) and from 576 till 900 ms post-stimulus (including late slow wave positivity). Event-related potentials for the standards of the oddball task were compared with the potentials of the same stimuli presented in the neutral condition. In addition, the classical comparison between the target and the standard in the oddball task was made. The first comparison was designed to isolate any effect of a change in the level of vigilance and attention due to involvement in the oddball task. This effect was evident as an increase in positivity that was smaller in the diazepam condition. The second comparison was designed to isolate the distinctive processing associated with task-relevant stimuli. This revealed that the P300 was reduced in the 250-574 ms window in the diazepam group. Both results suggest that cognitive processing of relevant stimuli is reduced by diazepam. Presumably, this is associated with the sedative effects of this drug. Consistent with this interpretation, subjects under the influence of diazepam made more omissions in the detection of targets in the oddball condition and had longer reaction times. In contrast to diazepam, the anxiolytic buspirone did not appear to have measurable effects on cognition.

Adult↗
PubMed1998

Region-specific changes in [3H]dizocilpine binding in diazepam-withdrawn rats.

In the present study, to clarify the role of the N-methyl-D-aspartate (NMDA) receptor in the appearance of diazepam withdrawal signs, the changes in [3H]dizocilpine binding in several brain regions from diazepam-withdrawn rats were investigated. Brain membranes were prepared 42-45 h after termination of diazepam treatment when maximal withdrawal signs were shown. The Bmax value for [3H]dizocilpine binding was significantly increased in cerebrocortical, but not hippocampal and cerebellar, tissues from diazepam-withdrawn rats, while the Kd value did not change in any group. Together with our previous finding that NMDA receptor antagonists potently suppress diazepam withdrawal signs, these results suggest that the upregulation of the NMDA receptor in the cerebral cortex may play an important role in the appearance of spontaneous withdrawal signs caused by discontinuation of chronic diazepam treatment.

Animals↗
PubMed1999

N-methyl-D-aspartate receptor activation regulates refractoriness of status epilepticus to diazepam.

Status epilepticus, prolonged intermittent or continuous seizure activity lasting 30 min or longer, is associated with high morbidity and mortality. The longer a seizure persists, the more refractory to treatment it becomes. The pilocarpine model of status epilepticus in rodents develops refractoriness to many first-line treatments as seizure duration increases, rendering it a good model to study refractory status epilepticus. This study was initiated to study the development of refractoriness of pilocarpine-induced status epilepticus to diazepam. Early pilocarpine-induced status epilepticus responded rapidly to diazepam treatment, whereas status epilepticus of longer duration became increasingly less responsive to treatment. Dizocilpine maleate-pretreated animals responded rapidly to diazepam treatment, even after 60 min of status epilepticus. Animals administered dizocilpine maleate at 15, 30 or 60 min after the onset of status epilepticus also demonstrated a rapid response to diazepam compared to pilocarpine-alone-treated animals. The longer the status epilepticus progressed prior to dizocilpine maleate injection, the longer the status epilepticus lasted after diazepam treatment. However, in all cases where dizocilpine maleate was administered, one injection of diazepam was able to terminate the status epilepticus, in contrast to the animals that did not receive dizocilpine maleate, in which the seizure was only attenuated. The results indicate that N-methyl-D-aspartate receptor activation plays a role in the seizure-induced refractoriness to benzodiazepines in status epilepticus, and blocking N-methyl-D-aspartate receptor activation converts refractory status epilepticus to a seizure responsive to benzodiazepine therapy. These findings offer insights into developing novel therapeutic interventions to improve the treatment of status epilepticus. Understanding the molecular mechanisms that mediate the effects of N-methyl-D-aspartate receptor activation on the development of resistance to treatment in status epilepticus will provide rational insights into more rapid methods to terminate seizure activity in this condition.

Animals↗
PubMed2001

The effect of surfactants on the skin penetration of diazepam.

The percutaneous permeation of diazepam was investigated in rat skin after application of a water-propylene glycol (50:50% v/v) using a diffusion cell technique. The effect of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on skin permeability were evaluated. Flux, K(p), lag time and enhancement ratios (ERs) of diazepam were measured over 10 h and compared with control sample (containing no surfactant). Furthermore, diazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of diazepam. Benzalkonium chloride which possessed the highest lipophilicity (logP=1.9) among cationic surfactants provided the greatest enhancement for diazepam flux (7.98-fold over control). CTAB (logP<1) at a concentration of 1% w/w exhibited no significant increase in flux of diazepam compared to control (1.16-fold over control). The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant to form micelles and is normally observed only if interaction between micelle and the drug occurs. The results showed that the nature of enhancer greatly influences cutaneous barrier impairment.

Administration, Cutaneous↗
PubMed1986

Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions.

To determine the optimum dosage schedule for intermittent rectal diazepam in suppository form for the prevention of recurrent febrile convulsions, we studied the pharmacokinetics of diazepam administered in repeated rectal doses. The plasma concentration-time data for diazepam on twice repeated rectal dosing with 0.5 mg/kg at 8-hour intervals in six infants showed that therapeutic plasma levels could be attained within 30 minutes and maintained for the first 24 hours. Most of the observed plasma diazepam levels were found to be within +/- one standard deviation of the values calculated from the pharmacokinetic parameters in six other infants with single rectal dosing. Computer-simulated plasma level profile suggested that plasma diazepam levels may reach the toxic range after administration of five or more doses. Twice repeated rectal dosing with 0.5 mg/kg of diazepam in suppository form at 8-hour intervals during the febrile period may be a rational approach for the prevention of recurrent febrile convulsions.

Diazepam↗
PubMed1999

Prehospital stability of diazepam and lorazepam.

Injectable benzodiazepines are commonly stocked on ambulances for use by paramedics. We evaluated the stability of lorazepam and diazepam as a function of storage temperature. Diazepam (5 mg/mL) and lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4 degrees C to 10 degrees C (refrigerated); 15 degrees C to 30 degrees C (on-ambulance ambient temperature); and 37 degrees C (oven-heated). High-performance liquid chromatography (HPLC) analyses of syringe contents were performed at 30-day intervals. After 210 days, the reduction in diazepam concentration was 7% refrigerated, 15% at ambient temperature, and 25% at 37 degrees C. The reduction in lorazepam concentration was 0% refrigerated, 10% at ambient temperature, and 75% at 37 degrees C. Whereas diazepam retained 90% of its original concentration for 30 days of on-ambulance storage, lorazepam retained 90% of its original concentration for 150 days. The decrease in lorazepam concentration correlated with an increase in the maximum ambient temperature in San Francisco. These results suggest that diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 degrees C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30 degrees C, more frequent stocking or refrigeration is required.

Ambulances↗
PubMed1992

[Effects of diazepam on mortality from acute chloroquine poisoning].

A retrospective study was carried out, over a twelve-year period, of all cases of acute chloroquine poisoning where more than 2 g of chloroquine had been taken. It included 386 patients; of these, 60 who had taken drugs other than chloroquine, and 17 who had ingested less than 1 g of the drug, were excluded. The remaining 309 patients were allocated to two groups: a "control group", consisting of the patients admitted between January 1973 and April 1980 (n = 146), and a "diazepam group", made up of those admitted from May 1980 to December 1989 (n = 163). The patients in the latter group had had the same symptomatic treatment as those in the control group, and had been routinely given a 0.5 mg.kg-1 bolus of diazepam on admission followed by 0.1 mg.kg-1.day-1 for every 100 mg of chloroquine supposed to have been ingested. Both groups were divided into three subgroups, those patients with cardiorespiratory arrest, and those with, and those without, symptoms on admission. No statistically significant difference was found between either the control and diazepam groups or between subgroups, concerning the distribution of age, sex, amount of chloroquine supposed to have been ingested, delay in hospital admission and death rate. However, there was a higher death rate in the asymptomatic subgroup not treated with diazepam than in the diazepam group. Therefore, the routine use of diazepam for the treatment of acute chloroquine poisoning does not seem to be justified in symptomatic cases and in those with inaugural cardiac arrest.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗