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PubMed1996

Preference for diazepam, but not buspirone, in moderate drinkers.

The purpose of the present study was to determine the preference for buspirone, an anxiolytic predicted to have minimal abuse potential, in comparison with diazepam in moderate drinkers. Preference for diazepam and buspirone was assessed in 55 moderate drinkers using a seven-session procedure consisting of four sampling sessions followed by three choice sessions. On each sampling session subjects ingested five capsules, one every 30 min. Color-coded capsules contained placebo on two sessions and drug on two sessions. Each drug capsule contained diazepam (4 mg) for 30 subjects and buspirone (5 mg) for 25 subjects. On choice sessions subjects chose whichever of the two color-coded capsules, i.e., drug or placebo, they wished to take. After ingesting one capsule, every 30 min they had the option of ingesting another capsule of the same color and content, for a maximum of seven capsules over the session (maximum of 28 mg diazepam or 35 mg buspirone). In the diazepam group 70% of subjects chose diazepam over placebo on at least two of the three choice sessions, whereas in the buspirone group only 24% of subjects chose buspirone over placebo on at least two sessions. Both diazepam and buspirone increased measures of sedation. Only diazepam increased ratings of liking and impaired performance, whereas only buspirone decreased ratings of feeling Friendly. These results replicate previous findings indicating that diazepam has reinforcing effects in moderate drinkers. Further, these results demonstrate the pharmacological specificity of this effect by showing that buspirone did not function as a reinforcer under these same conditions.

Adult↗
PubMed1998

Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice: evidence for upregulation of NMDA receptors.

The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during diazepam withdrawal in mice, using behavioral and biochemical approaches. The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but also to sigma receptors, the present study also investigated the effects of sigma receptor ligands. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5 mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.

Animals↗
PubMed2003

Diazepam produces disinhibitory cognitive effects in male volunteers.

RATIONALE: Diazepam has well known amnestic and sedative effects but effects on fronto-executive function remain largely uninvestigated, especially on neuropsychologically validated tests of risk taking and orbitofrontal cortex function. OBJECTIVES: We aimed to determine the impact of diazepam on a variety of executive tasks. METHODS: The effects of 5, 10 and 20 mg of diazepam on a battery of neuropsychological tests were investigated using a randomised, double blind, placebo-controlled design. Seventy-five adult men were recruited. The Rogers et al. (1999b) test of risk-taking was given along with tasks from the CANTAB battery. RESULTS: Diazepam impaired performance on the Tower of London test of planning, without influencing visual pattern recognition memory. Subjects who had taken diazepam made more risky choices on the risk-taking task. On two speeded reaction time tasks diazepam impaired discrimination sensitivity and increased the bias to respond. CONCLUSIONS: In contrast to the well-known sedative effects of diazepam, we demonstrate disinhibitory effects on two speeded reaction time tasks. Our results show that diazepam can impair performance on reaction time tasks both by impairing sensitivity and by increasing the bias to respond. Furthermore diazepam impaired performance on tests of planning and risky decision making that depend predominantly on dorsolateral and orbitofrontal regions of the prefrontal cortex, respectively.

Adult↗
PubMed1977

Diazepam blockade of repetitive action potentials in skeletal muscle fibres. A model of its membrane action.

Diazepam inconcentrations of 10(-6) and 10(-5) M effectively blocks trains of action potentials (AP) in individual rat diaphragm muscle fibres 'in vitro'. Single APs, evoked and recorded intracellularly with double microelectrodes, were not affected by diazepam. Trains of APs, evoked in diaphragm fibers in a SO42-- -medium (Cl-- -free), were not affected by diazepam. Diazepam decreased the dependence of the membrane resting potential of muscle cells in chloride media on elevated external potassium whereas no effect was observed in SO42-- --Cl-- -free saline. Similar to in the rat diaphragm, diazepam blocked the trains of AP of individual muscle fibres in the frog sartorius muscle (Cl-- -medium). Diazepam did not affect the spontaneous fibrillatory APs recorded extracellularly from rat gastrocnemius muscles 10 days after denervation. Diazepam apparently increases the resting permeability of the muscle fibre memebrane for chloride ions. In the presence of the drug, the higher permeability for Cl- diminishes the depolarization caused by the potassium released and accumulated in the vicinity of the membrane in the course of AP. The muscle fibre membrane thus does not respond by repetitive activity when partially depolarized and only one AP can be evoked when diazepam is present. It is suggested that similar changes in Cl-- permeability may occur in brain excitable structures after diazepam administration and may account for some of the therapeutic effects of the drug.

Action Potentials↗
PubMed1982

Diazepam and pentobarbital dependence in the rat.

Diazepam (100-133 mg/kg/day), administered chronically through a gastric fistula, and pentobarbital (ca 692 mg/kg/day), administered chronically in food, were studied for their dependence producing properties in Sprague-Dawley female rats. The diazepam abstinence syndrome was apparent 10 to 20 hours after withdrawal, persisted for over 60 hours and consisted of poker tail, explosive awakenings, digging in sawdust, jerks, tremors, wet dog shakes, hostility, decreased food and water consumption and weight loss. The pentobarbital abstinence syndrome came on rapidly peaking within 10 hours and was largely over by 16 hours. The pentobarbital abstinence syndrome differed from diazepam's by the presence of grand mal, clonic and atypical convulsions. Diazepam completely and in a dose related way suppressed the diazepam abstinence syndrome. Similarly pentobarbital suppressed the pentobarbital abstinence syndrome. The signs which could be suppressed in a dose related manner were different for the diazepam and pentobarbital abstinence syndromes. Diazepam only partially suppressed the pentobarbital abstinence syndrome and pentobarbital only partially suppressed the diazepam abstinence syndrome. These data indicate that diazepam and pentobarbital produce different types of dependencies in the rat and are not equivalent in suppressing signs of abstinence.

Animals↗
PubMed1985

A microgram dose of diazepam produces specific inhibition of ambulation in the rat.

There is considerable consistency in the experimental literature showing that non-sedating doses of benzodiazepines can enhance the consumption of food, water and salt solutions. It is of great interest, therefore, that in a previous report low dose treatments with diazepam were found to significantly suppress the level of consumption of a palatable 0.005 M sodium saccharin solution in nondeprived male rats. The present study was designed to elucidate the behavioral characteristics of the inhibitory action of low dose diazepam treatments. Food consumption and general activity measures were chosen for analysis to examine the possibilities that low dose diazepam treatments might suppress ingestive behavior in a general way, or that the treatments might affect nonconsummatory responses including components of spontaneous motor activity. The results of two experiments succeeded in locating a highly specific inhibitory effect produced by 100 micrograms/kg diazepam. First, food consumption was not inhibited. Instead, 1.0 mg/kg diazepam produced significant elevations in food intake in both food-deprived and nondeprived animals. Second, vertical activity (rearing) and fine body movements were unaffected over the dose-range 0.1-3.0 mg/kg diazepam. Hence, low dose treatments with diazepam did not produce a generalised nonspecific behavioral depression. However, 100 micrograms/mg diazepam significantly inhibited coarse activity (measured automatically) and the corresponding ambulation measure (recorded by direct observation). The effect was present throughout a 1 hr test period and did not interact with the declining baseline level of activity. The results therefore confirm the presence of low dose diazepam-induced behavioral inhibition in quite a different context from the saccharin solution consumption study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Diazepam self-administration and resistance to extinction.

Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.

Animals↗
PubMed1994

Dissipation of contingent tolerance to the anticonvulsant effect of diazepam: effect of the criterion response.

The effect of convulsive stimulations on the dissipation of tolerance to the anticonvulsant effect of diazepam was investigated using the kindled-convulsion model. Amygdala-kindled rats were rendered tolerant to diazepam's anticonvulsant effect by 25 "bidaily" (one/48 h) diazepam injections (2.5 mg/kg), each followed 1 h later by a convulsive stimulation. They were then divided into nine groups for the tolerance-dissipation phase of the experiment. Of the nine groups, three received bidaily control handling for one trial, three trials, or seven trials; three received bidaily saline injections, each 1 h before a convulsive stimulation, for one, three, or seven trials; and three received bidaily diazepam injections, each 1 h after a convulsive stimulation, for one, three, or seven trials. Finally, each rat received a tolerance-retention test (i.e., a diazepam injection followed 1 h later by a convulsive stimulation) 48 h after its last tolerance-dissipation trial. The tolerance dissipated gradually but completely over the 4-, 8-, and 16-day test intervals in the rats that received a convulsive stimulation before each injection during the tolerance-dissipation phase, whether they were injected with saline or diazepam; in contrast, tolerance did not dissipate in the rats that received saline injections but no stimulations. Remarkably, the discontinuance of the bidaily diazepam injections, even for 16 days, was not sufficient to dissipate the tolerance that had developed to diazepam's anticonvulsant effect; nor was the continuation of the bidaily diazepam injections sufficient to keep tolerance from dissipating.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cholinergic actions of diazepam and atropine sulfate in soman poisoning.

The effectiveness of diazepam alone or in the presence of atropine sulfate in reversing soman-induced convulsions, inhibition of blood and brain cholinesterase (ChE) activity, and elevation of brain acetylcholine (ACh) and choline (Ch) concentrations in rats was studied. Diazepam (5 mg/kg, IM) blocked the convulsive activity of soman (100 micrograms/kg, SC) whereas atropine sulfate (12 mg/kg, IM) did not. Inclusion of atropine sulfate enhanced the anticonvulsant effects of diazepam. Neither diazepam nor atropine sulfate alone affected ChE activity in the blood and brain of rats, nor did they alone, or in combination, reverse the ChE inhibition induced by soman. Diazepam by itself caused an increase in ACh concentrations in the striatum and a decrease in Ch concentrations in the cortex and striatum. On the other hand, atropine sulfate produced a decrease in ACh and an increase in Ch concentrations in these two brain regions. With combined treatment, diazepam reversed the effect of atropine sulfate on brain ACh and Ch concentrations. Diazepam attenuated the soman-induced elevation of ACh and Ch concentrations in most of the brain regions studied, while atropine sulfate did not. Only when diazepam was given concurrently with atropine sulfate did the elevated brain ACh or Ch concentrations induced by soman return to normal. These results suggest that the anticonvulsant activity of diazepam in soman poisoning may be partially related to its action on presynaptic cholinergic mechanism.

Acetylcholine↗
PubMedDate not supplied

Activity in a modified open-field apparatus: effect of diazepam and prenatal stress.

We examined the effect of prenatal stress exposure on sensitivity to diazepam. The stress exposure consisted of handling pregnant rats 5 minutes daily from the 14th to 21st day of gestation. Male offspring were tested at 60 days of age in a modified open-field apparatus 30 minutes after injection with diazepam (0, 1, 5 mg/kg). The 5 mg/kg dose of diazepam depressed the frequency and duration of crossover, rearing, headpoke and corner activities. Rearing was not affected by the 1 mg/kg dose of diazepam. Defecation was increased by the 1 mg/kg dose, but was decreased by 5 mg/kg of diazepam. Prenatal stress exposure altered responsiveness to diazepam on only crossover activity and on defecation. Prenatally stressed animals exhibited an increase in crossover at the low dose of diazepam, while control offspring were insensitive to this dose level. Also, there were more boli in prenatally stressed rats treated with 1 mg/kg diazepam, while the 5 mg/kg dose of the drug decreased the number of boli. The other measures showed a trend in the same direction but the differences were not statistically significant. Thus our results indicate that prenatal stress has very specific effects on the sensitivity of adult offspring to diazepam.

Animals↗
PubMed2005

Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats.

The benzodiazepine diazepam impairs memory and long-term potentiation (LTP) in the hippocampus. Here, we investigate the effect of diazepam on LTP of C-fiber evoked field potentials in spinal dorsal horn, which is relevant to pathological pain. LTP of C-fiber evoked field potentials was recorded in the superficial layers of spinal dorsal horn in urethane-anesthetized Sprague--Dawley rats. Diazepam was applied locally at the recording spinal segments before and after LTP induction by tetanic stimulation. We found (1) Diazepam completely blocked LTP induction. (2) Diazepam and midazolam reversed spinal LTP, when applied at 30 min after LTP induction and depressed but could not reverse spinal LTP, when applied at 3 h after LTP induction. (3) Pretreatment with benzodiazepine receptor antagonist flumazenil or GABA(A) receptor antagonist bicuculline completely blocked the inhibitory effects of diazepam on spinal LTP. In contrast, when the inhibitory effect of diazepam was fully established, neither of these antagonists was capable of reversing the inhibition by diazepam. (4) Spinal application of the GABA(A) receptor agonist 3-amino-1-propanesulfonic acid (3-APSA) at a dose of 50 microg, produced a transient inhibition of spinal LTP. These results suggest that diazepam might prevent and depress spinal plastic change produced by noxious stimulation via activation of the GABA(A) -benzodiazepine receptor complex.

Animals↗
PubMed1998

Inhibition of morphine tolerance and dependence by diazepam and its relation to mu-opioid receptors in the rat brain and spinal cord.

We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the development of morphine tolerance and dependence. We have now analyzed mu-opioid receptors in rats treated with morphine and diazepam for 5 days by using [3H]-DAMGO for binding studies. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b.wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5). There was an up-regulation of mu-receptor (Bmax increased) in the spinal cord of morphine tolerant (+139%) and dependent (+155%) rats compared to saline treated animals. Diazepam treatment abolished the up-regulation of mu-receptors in spinal cord of morphine treated rats. In the cortex, Bmax was not affected in morphine tolerant or dependent rats but it decreased by 38% in morphine tolerant and 65% in morphine dependent rats treated with diazepam. The Kd of mu-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the Kd of mu-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These results suggest that diazepam treatment antagonizes the up-regulation of CNS mu-receptors observed in morphine tolerant rats. In addition, morphine tolerance and dependence may be associated with conversion of mu-opioid receptors to mu-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treated with diazepam.

Analgesics, Opioid↗
PubMed1999

Cross-sensitivity between isoflurane and diazepam: evidence from a bidirectional tolerance study in mice.

We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity to diazepam. Mice were divided into four groups: group 1, treated with diazepam, 10 mg/kg i.p. twice daily; group 2, vehicle-treated controls; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (HWT). All control mice but only 10% of the diazepam-treated mice failed the HWT. Groups 1 and 2 were then exposed to increasing concentrations of isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7+/-0.7%, compared with 0.6+/-0.1% in controls (group 2) (P<0.001); the ED50 was 0.75% vs. 0.65%. Group 1 mice lost the righting reflex at 0.94+/-0.07% isoflurane vs. 0.87+/-0.06% in group 2 (P<0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175+/-161 s in group 1 vs. 343+/-275 s in group 2 (P<0.02). Twenty-four hours after the last of the repeated exposures to isoflurane, we examined the responses of groups 3 and 4 to increasing concentrations of isoflurane. Mice in group 3 lost the righting reflex at 1.0+/-0.06% isoflurane vs. 0.9+/-0.04% in controls (group 4) (P<0.001); the ED50 was 0.96% vs. 0.85%. Recovery time was 113+/-124 s vs. 208+/-126 s in groups 3 and 4 (P<0.09). Diazepam, 3 mg/kg i.p. administered to groups 3 and 4, caused loss of the HWT reflex in 33% of group 3 mice and in 82% of controls (group 4) (P<0.001). It appears that prolonged exposure to both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.

Administration, Inhalation↗
PubMed1999

Effects of diazepam on extracellular brain neurotransmitters in pilocarpine-induced seizures in rats.

The present study was undertaken to gain insights into the mechanism of action of diazepam in focally-evoked pilocarpine-induced seizures by concomitantly assessing the changes produced in the extracellular levels of glutamate, GABA (gamma-aminobutyric acid) and dopamine. In vivo microdialysis, coupled to continuous monitoring of electrocorticographic (ECoG) recordings, was performed in freely moving rats. Intrahippocampal perfusion with 10 mM pilocarpine (40 min, 2 microl/min) produced limbic seizures. A single dose of intraperitoneal diazepam (5 mg/kg) was administered 2 h after pilocarpine perfusion was started. Dialysates were sampled both from hippocampus and cerebellum and analysed by microbore liquid chromatography. Diazepam produced instant inhibition of behavioural and ECoG seizure activity. Pilocarpine-induced increases in the extracellular levels of glutamate and dopamine in hippocampus were promptly reduced by diazepam. No concurrent alterations in pilocarpine-induced increases in the extracellular levels of GABA in either hippocampus or cerebellum were seen. Pilocarpine enhanced cerebellar glutamate levels only transiently and levels returned to baseline before diazepam administration. No further changes in cerebellar glutamate levels were observed with diazepam. Our findings suggest that the anti-convulsant action of diazepam against pilocarpine-induced seizures is associated with a prompt attenuation of extracellular hippocampal glutamate overflow without concurrent alteration of pilocarpine-induced increases in endogenous GABA levels. Diazepam also significantly decreased pilocarpine-induced increases in extracellular dopamine levels within the hippocampus. No immediate alterations of the basal levels of the neurotransmitters monitored were observed with diazepam.

Animals↗
PubMed1996

Reversible modification of GABAA receptor subunit mRNA expression during tolerance to diazepam-induced cognition dysfunction.

Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABAA receptors cause anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test, diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABAA receptors, such as imidazenil, failed to induce amnesia, even if administered at doses five times higher than those equipotent to a standard anticonvulsant dose of diazepam (17.6 mumol/kg/os). After discontinuation of 14 days' treatment with vehicle, diazepam, or imidazenil (three times daily with increasing doses starting from 17.6 mumol/kg/os for diazepam and 2.5 mumol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of diazepam with the persistence of the changes in the context of four (alpha 1, alpha 5, gamma 2L, gamma 2S) GABAA receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30-50%) in the expression of mRNAs encoding for alpha 1 gamma 2L, gamma 2S GABAA receptor subunits, an increase, by approximately 30%, of the expression of mRNA of the alpha 5 subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of mRNA, of the alpha 1 subunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control values 72 hr after termination of the long-term treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABAA receptor subunit mRNA expression were found in rats undergoing long-term treatment with imidazenil.

Animals↗
PubMed1983

Diazepam loading: simplified treatment of alcohol withdrawal.

Alcohol withdrawal therapy can be simplified with a loading dose of diazepam, taking advantage of the kinetic tapering afforded by the drug's long t 1/2s and its metabolites, and of the effectiveness of nonpharmacologic maneuvers. In a double-blind trial, 50 inpatients in moderate to severe alcohol withdrawal received 20 mg oral diazepam and supportive care (n = 25) or placebo and supportive care (n = 25) every 2 hr until they were asymptomatic. Fifty-six percent of patients responded to placebo within 5 +/- 2.9 hr (mean +/- SD), whereas 72% responded to initial diazepam within 6.3 +/- 3.9 hr. Patients treated with diazepam had more rapid and greater improvement than those treated with placebo. Patients who did not respond to six doses of diazepam received further (unblinded) diazepam, 20 mg, every 1 to 2 hr. All patients who did not initially respond (n = 18) improved after more diazepam. Thus all patients who received diazepam (n = 36), during the experimental phase or subsequently, were effectively treated. There were no adverse effects. The median number of 20-mg diazepam doses to treat alcohol withdrawal were three, given over a period of 7.6 hr (range = 1 to 12 and 0.33 to 45 hr). Complications occurred only in those who received placebo during the experimental phase, indicating that delay in therapy may be responsible for the appearance of complications in alcohol withdrawal.

Adult↗
PubMed1989

The disposition and placental transfer of diazepam in cesarean section.

The disposition parameters and placental transfer of diazepam were determined from blood and both plasma total and free concentration data in five women who had not undergone labor and who received diazepam (5 mg intravenously for 2 minutes) 1 1/2 to 3 hours before cesarean section at term. All patients exhibited smooth log plasma free concentration-time profiles. In contrast, marked increases in plasma total (approximate 50% increase) and blood (approximate 40% increase) diazepam concentrations occurred at delivery. The plasma total and blood concentration fluctuations were associated with reciprocal variations in diazepam percent free in plasma. For each patient there was a substantial increase in plasma nonesterified fatty acid (NEFA) concentration during the surgical period. There was a significant correlation (p less than 0.02) between diazepam percent free and plasma NEFA concentration on the day of delivery, suggesting that the fluctuations in percent free, and hence plasma total and blood diazepam concentrations, were mediated in part by variations in plasma NEFA concentration. Disposition parameters were calculated for four of the patients; the mean free plasma clearance of diazepam was 42.5 ml/min/kg, similar to the mean value reported previously for nonpregnant women of comparable age. For each mother-infant pair at delivery the ratio of total plasma diazepam concentration in umbilical vein plasma to that in maternal vein plasma was considerably greater than unity (mean +/- SD = 1.73 +/- 0.47), whereas the corresponding ratio for free plasma diazepam concentration was near unity (0.92 +/- 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype.

1. The disposition of diazepam and desmethyldiazepam was studied in 21 healthy male Chinese subjects who were phenotyped with mephenytoin. Four poor metabolizers (PM) were identified by phenotyping with mephenytoin and by genotyping for CYP2C19. 2. Serum diazepam and desmethyldiazepam concentrations were measured by high performance liquid chromatography in samples drawn up to 24 days after administration. 3. The plasma elimination half-lives of diazepam (100.8 +/- 32.3 h) and desmethyldiazepam (219.9 +/- 62.7 h) in PMs were significantly longer than those (34.7 +/- 23.0 h for diazepam, 103.1 +/- 25.9 h for desmethyldiazepam) of the 17 phenotyped extensive metabolizers (EM), and those (30.8 +/- 24.9 h for diazepam, 103.1 +/- 27.5 h for desmethyldiazepam) of the five genotyped EMs. 4. The mephenytoin S/R ratios were significantly correlated with the plasma half-lives of diazepam (r = 0.543, P < 0.05) and desmethyldiazepam (r = 0.522, P < 0.05), and with the clearance (r = -0.524, P < 0.05) of diazepam in 21 subjects. 5. These results are compatible with the conclusion that both diazepam and desmethyldiazepam are metabolized by cytochrome P450 CYP2C19 in the Chinese population. 6. The mephenytoin S/R ratios in nine EMs who drank alcohol frequently were significantly higher than those of seven EMs who were non-drinkers, but the plasma kinetics of diazepam and desmethyldiazepam were not significantly different between the two groups. The explanation for these finding is not clear.

Asian People↗