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PubMed1996

Treatment, discontinuation, and psychomotor effects of diazepam in women with generalized anxiety disorder.

Twenty-one women with generalized anxiety disorder (GAD) participated in a 6-week, double-blind, placebo-controlled trial to assess the treatment and abrupt withdrawal effects of diazepam on psychic and somatic symptoms of anxiety. The results confirmed those of previous studies reporting that (1) clinical doses of diazepam are effective in attenuating the symptoms of generalized anxiety to a greater extent than placebo during the first 3 weeks of treatment; (2) somatic symptoms are more responsive to diazepam treatment than psychic symptoms; and (3) patients taking diazepam exhibit increased anxiety upon abrupt withdrawal of medication. This finding, combined with the fact that diazepam discontinuation did not produce withdrawal effects in non-anxious volunteers, suggests that diazepam discontinuation after 6 weeks results in rebound anxiety rather than a physical withdrawal syndrome. Diazepam did not improve psychomotor performance in GAD patients. Psychomotor impairment after 6 weeks of diazepam was similar to that seen in nonanxious volunteers.

Adult↗
PubMed2000

A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder.

In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66%). At intake and baseline, after a 1-week placebo washout, the patient was required to have a Hamilton Rating Scale for Anxiety score of > or =20. Major adverse events for both abecarnil and diazepam were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical improvement data showed that both abecarnil and diazepam produced statistically significantly more symptom relief than did placebo after 1 week of treatment. At 6 weeks treatment (using last observation carried forward analysis), however, only diazepam still differed significantly (p < 0.01) from placebo. High placebo response (56% moderate to marked global improvement) at 6 weeks, as well as a slightly lower nonsignificant improvement rate observed with abecarnil, a partial y-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA agonist, most likely contributed to our findings. Finally, taper results showed that only diazepam and not abecarnil caused the presence of temporary discontinuation symptoms, but only in patients who had been treated for at least 12 weeks.

Adolescent↗
PubMed2000

Specificity of effects of chronically administered diazepam on the responding of rats under two different spaced-responding schedules.

Lever pressing of rats was maintained in different chambers during two different sessions each day. At 0900 h, responding was maintained under a two-component multiple schedule in which responses initiated an interval that had to elapse before delivery of food (time delay of 20 s and 40 s). In this schedule, a 'response-pause' sequence preceded reinforcers, and acutely administered diazepam only decreased responding. At 1400 h, responding by the same subjects was maintained under a different two-component multiple schedule, in which individual responses initiated an interval that had to be terminated by another response before delivery of food (DRL 20 s and 40 s). In this second schedule, a 'response-pause-response' sequence preceded reinforcers, and acutely administered diazepam increased responding. After studying the acute behavioral effects of diazepam during each separate 'timing' schedule, animals systematically received 1.7 mg/kg per day diazepam 2-5 min prior to their different schedule components, in order to study the influence of reinforcement contingency on the chronic effects of this drug. Diminution of the initial effects of diazepam during daily drug administration prior to DRL 20 s responding did not extend to DRL 40 s responding or to time-delay responding, and tolerance did not develop at all for time-delay responding. When diazepam was again administered after all the daily schedules for approximately 1 month, and then given before the individual DRL schedules, DRL responding was increased again as it had been prior to chronic drug administration. These results suggest that the behavioral effects of acutely administered diazepam are influenced by different 'timing' requirements, and that the behavioral effects of chronically administered diazepam are influenced by 'timing' requirements and by drug- and chamber-related stimuli.

Animals↗
PubMed1991

Thiamylal- and halothane-sparing effect of diazepam in dogs.

The thiamylal- and halothane-sparing effect of diazepam was studied in two experiments using 32 conditioned dogs. Twenty-four dogs received 0.05, 0.1 or 0.2 ml/kg diazepam or 0.9% saline (placebo) prior to the administration of thiamylal sodium i.v. Eight dogs received 0.1 or 0.2 mg/kg diazepam i.v. or placebo prior to or during halothane anesthesia. All three doses of diazepam significantly decreased the amount of thiamylal required to allow orotracheal intubation. The 0.2 mg/kg i.v. dose of diazepam produced the most significant effects. Premedication of dogs with diazepam did not reduce the concentration of halothane required to maintain anesthesia. The administration of 0.1 and 0.2 mg/kg diazepam i.v. during halothane anesthesia decreased the concentration of halothane required to maintain anesthesia. These studies demonstrate that diazepam reduces the amount of thiamylal required for orotracheal intubation, and when given intra-operatively reduces the concentration of halothane required to maintain anesthesia.

Animals↗
PubMed1996

The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam.

The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.

Adolescent↗
PubMed1977

Metabolic basis for the supra-additive effect of the ethanol-diazepam combination in mice.

1 The comination of ethanol and diazepam elicits additive or supra-additive pharmacological effects in animals and humans. Since the mouse appeared to be a reasonably good animal model for man, this species was examined to determine if a biochemical basis for these effects could be established.2 The effect of ethanol (3 g/kg, orally), administered 0.5 h before [(14)C]-diazepam (5 mg/kg, orally), on the pharmacokinetics of diazepam in male Swiss Webster mice was examined.3 At 4, 6, 8 and 12 h after dosing, blood levels of (14)C were higher in ethanol pretreated mice than in vehicle pretreated controls. A tissue distribution study indicated that ethanol had similar effects on levels of (14)C in most tissues at 2, 6 and 12 hours.4 Both pretreated and control mice eliminated approximately 25% of the dose of isotope in the urine and 50% in the faeces by 48 hours.5 Biliary excretion was the major route of clearance in mice in which the bile ducts had been cannulated and ethanol reduced excretion at all time periods examined up to 12 hours.6 Oxazepam (the glucuronide in bile) and desmethyl diazepam were the major metabolites identified in bile, plasma and brain. Ethanol reduced oxazepam levels but increased desmethyl diazepam levels, suggesting that 3-hydroxylation of desmethyl diazepam was inhibited by ethanol.7 The accumulation of the pharmacologically active desmethyl diazepam in the brains of ethanol pretreated mice offers an explanation for the supra-additive effect of the ethanol-diazepam combination on motor coordination.

Animals↗
PubMed1988

Effects of non-sedative anxiolytic drugs on responses to GABA and on diazepam-induced enhancement of these responses on mouse neurones in cell culture.

1. Intracellular microelectrode recording techniques were performed on mouse spinal cord and cerebral hemisphere neurones grown in primary dissociated cell culture. The effects of several anxiolytics applied by local pressure ejection on responses to gamma-aminobutyric acid (GABA) evoked by iontophoresis were investigated. Responses to GABA were depolarizing since intracellular chloride ion concentration was increased by injection from potassium chloride (3M)-filled recording micropipettes and neurones were held at large negative membrane potentials (-70 to -90 mV). The agents studied were six 'non-sedative anxiolytics', CL 218,872 (3-methyl-6-(3-trifluoromethyl-phenyl)1,2,4-triazolo(4,3-b) pyridazine), PK 8165 (2-phenyl-4-(2-(4-piperidinyl)ethyl)-quinoline), PK 9084 (2-phenyl-4-(2-(3-piperidinyl)ethyl)-quinoline), CGS 9896 (2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one) , ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl-beta-carboline-3-beta-carboxylate), buspirone (8-4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl-8-azaspiro[4.5]decane- 7,9- dione), and two sedative anxiolytics, diazepam and zopiclone [( 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin- 5- yl]4-methyl-1-piperazinecarboxylate). 2. Direct effects on responses to GABA were studied for all drugs applied in varying concentrations. For the drugs which significantly altered responses to GABA, the effects of the benzodiazepine receptor antagonists Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)-(1,4)benzodi azepine - 3-carboxylate) and CGS 8216 (2-phenylpyrazolo(4,3-c)-quinolin-3(5H)-one) were evaluated. For the drugs devoid of significant direct effect on responses to GABA, the influence on diazepam-induced enhancement of responses to GABA was evaluated. 3. Diazepam, zopiclone and CL 218,872 concentration-dependently and reversibly enhanced responses to GABA. Maximal enhancement was 82% for diazepam (500 nM), 64% for zopiclone (10 microM) and 20% for CL 218,872 (10 microM). PK 8165 effects varied with concentration, enhancing responses to GABA (up to 18%) at nM concentrations and reducing responses to GABA (up to 90%) at microM concentrations. CGS 9896, ZK 9126, PK 9084 and buspirone, in concentrations ranging from 1 nM to 10 microM, lacked significant direct effects on responses to GABA. 4. The enhancing effects of diazepam, zopiclone, CL 218,872 and PK 8165 were antagonized by Ro 15-1788. However, the reducing effect on responses to GABA of PK 8165 at microM concentrations was not antagonized by CGS 8216. CGS 9896 and ZK 91296 concentration-dependently blocked the diazepam-induced enhancement of responses to GABA. However, PK 9084 and buspirone did not antagonize the diazepam-induced enhancement of responses to GABA. 5. These results indicate that diazepam and zopiclone may be full agonists, CL 218,872 and PK 8165 are partial agonists, and CGS 9896 and ZK 91296 are pure antagonists at benzodiazepine receptors. On the other hand, PK 9084 and buspirone do not interact with benzodiazepine receptors.

Animals↗
PubMed1988

Withdrawal reactions to diazepam in combined imipramine/diazepam treatment of primary nonagitated depressed outpatients.

Twenty-seven outpatients who had primary nonagitated depression that had been treated for 3.5 months with imipramine were included in the study. Of these, 14 patients were given additional diazepam treatment (10 mg/day) and 13 patients got placebo. The additional medication was stopped, and withdrawal reactions were observed after two weeks. The depression scores (both global evaluation and CPRS) increased significantly in the diazepam group, without any changes in the placebo group. Eleven patients in the diazepam group and four in the placebo group reported their condition as impaired after discontinuing their additional medication. Four patients in the placebo group and none in the diazepam group reported improvement. The level of working activity decreased significantly in the diazepam group and increased in the placebo group. The serum level of imipramine decreased in the placebo group (P = 0.07), but not in the diazepam group. Serum levels of desipramine decreased significantly in both groups (P less than 0.05). Our study indicates that the discontinuation of diazepam, even when given in moderate dosage over a relatively short period of time, may cause withdrawal reactions in combined antidepressant/diazepam treatment. This may be caused by a possible tendency for the depression to become chronic. Such chronicity may be the reason for secondary dependency to diazepam.

Clinical Trials as Topic↗
PubMed1990

Diazepam attenuates morphine antinociception test-dependently in mice.

The influence of diazepam on the antinociceptive effect of morphine was studied using four different nociceptive tests in mice. In the tail flick test, diazepam induced a dose-dependent reduction of the morphine effect, with an almost total reversed morphine effect following diazepam 2 mg/kg. The effect could not be explained by altered tail skin temperature or pharmacokinetic changes. Diazepam 1 mg/kg and higher induced sedation and significantly impaired the performance in a rotarod test, a dose of 0.5 mg/kg diazepam was therefore used in the other nociceptive tests. This dose of diazepam significantly attenuated the antinociceptive effect of morphine in the constant temperature hot plate test and the tail flick test. In the increasing temperature hot plate test and in the formalin test, no effect of diazepam on the nociceptive effect of morphine was observed. The results indicate that diazepam antagonizes the effect of morphine dependent upon the test employed. No antagonism could be observed in tests with a long-lasting stimulus, and a response integration probably at a rather high level in the CNS. In the two tests showing antagonism, the stimulus is more short-lasting, and at least for the tail flick test, the integration takes place at a lower level in the CNS.

Analgesics↗
PubMed1990

Effects of diazepam on the carotid sinus baroreflex control of circulation in rabbits.

To examine the effects of diazepam on the carotid sinus baroreflex control of circulation, bilateral carotid occlusion was performed on 14 conscious rabbits with aortic denervation. The responses of mean arterial pressure, heart rate, cardiac output and total peripheral resistance were obtained. The haemodynamic responses to carotid occlusion were evaluated at cumulative doses of 0.5 and 1.0 mg kg-1 of diazepam. The administration of diazepam decreased cardiac output and increased total peripheral resistance significantly, but did not affect the arterial pressure and heart rate. The response of total peripheral resistance to carotid occlusion was significantly increased from 0.118 +/- 0.018 (mean +/- SE) to 0.154 +/- 0.026 mmHg min ml-1 at 1.0 mg kg-1 of diazepam. The heart rate response was attenuated significantly from 41 +/- 5 to 24 +/- 4 beats min-1 at 1.0 mg kg-1 of diazepam. Diazepam did not alter the response of arterial pressure to carotid occlusion. We suggest that the dissociated effects of diazepam on the reflex control of circulation reflect the dissociated influences of diazepam on the central sympathetic and vagal-mediated pathways.

Animals↗
PubMed2004

The Discriminative stimulus effects of gamma-hydroxybutyrate and related compounds in rats discriminating baclofen or diazepam: The role of GABA(B) and GABA(A) receptors.

The discriminative stimulus effects of gamma-hydroxybutyrate (GHB) can be mimicked by GABA(A) receptor-positive modulators (e.g., diazepam) and GABA(B) receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors gamma-butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABA(A) receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABA(B) receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABA(B), mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABA(A) mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.

Adjuvants, Anesthesia↗
PubMed2002

Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys.

The present study examined how daily treatment with the benzodiazepine (BZ) diazepam modifies the effects of positive modulators acting at different sites on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABA(A) modulators were administered alone or in combination with acute or chronic diazepam to rhesus monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus-shock termination (SST). There was mutual antagonism between the rate-decreasing effects of diazepam (5.6 mg/kg, p.o.) and high efficacy BZ site negative modulators [ethyl beta-carboline-3-carboxylate (beta-CCE), methyl beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (DMCM)]. Antagonism of beta-CCE, beta-CCM, and DMCM by diazepam was markedly reduced in monkeys receiving diazepam daily. In contrast, daily diazepam treatment enhanced the rate-decreasing effects of Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and flumazenil. Chronic diazepam elicited cross-tolerance to the BZ triazolam and not to the barbiturate pentobarbital or the neuroactive steroid pregnanolone. These results suggest that tolerance to the rate-decreasing effects of BZs is not accompanied by cross-tolerance to positive GABA(A) modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABA(A) modulators during chronic diazepam treatment appeared to be related to negative efficacy and not clearly related to the precipitation of withdrawal for all drugs. These results indicate that changes in sensitivity to the behavioral effects of drugs that act at different sites on the GABA(A) receptor complex might be especially useful for identifying and characterizing the functional consequences of GABA(A) receptor heterogeneity.

Animals↗
PubMed1987

Differential effects of diazepam on rat hindlimb muscles.

The effects of diazepam on internal membrane potential and action potentials and the isometric twitch and tetanus have been examined in rat fast-twitch (extensor digitorum longus) and slow-twitch (soleus) fibres. Low concentrations of the drug encountered during clinical usage (about 10 microM) had no effect on the membrane electrical properties or contractile properties of the fibres. Higher concentrations of diazepam (100-800 microM) induced changes in action potentials and excitation-contraction coupling but not in the resting membrane potential. After exposure to diazepam there was a rapid, concentration-dependent increase in twitch tension, which was attributed to an effect on excitation-contraction coupling, since the action potential and membrane potential were not altered. Soleus fibres were most sensitive to the potentiating action of diazepam. The decay of the tetanus was prolonged in both types of fibre, which indicated that diazepam blocked calcium uptake by the sarcoplasmic reticulum. Unexpectedly, the decay of isometric twitches was sensitive to diazepam only in soleus fibres, suggesting that calcium uptake was rate-limiting for tension relaxation in slow- but not fast-twitch fibres. The amplitude of the twitch and tetanus fell below control levels after prolonged exposure to diazepam, and there was a parallel reduction in action potential overshoot, especially during tetanic stimulation. Fast-twitch fibres were most susceptible to the depressant effect of diazepam.

Action Potentials↗
PubMed1999

Evaluation of treatment of hyperemesis gravidarum using parenteral fluid with or without diazepam. A randomized study.

OBJECTIVE: Hyperemesis gravidarum is a relatively unknown disease, and is generally self-limiting. In some women the symptoms are so severe as to threaten the health of the mother and fetus. Therapies proposed for hyperemesis gravidarum are therefore rather empirical. Medical treatment includes parenteral fluid replacement and nutrition, electrolytes, antiemetics, vitamins, sedation and psychological counseling. Diazepam and benzodiazepines have been widely studied in pregnancy but the results are contradictory. The aim of the present study was to investigate the efficacy of parenteral fluids with vitamins, with or without diazepam sedation. METHODS: Fifty women with hyperemesis gravidarum were enrolled in the study. They were treated with infusions of normal saline, glucose, vitamins and randomly with diazepam. RESULTS: The results show that the mean stay in the hospital was shorter in the diazepam group: 4.5 +/- 1.9 vs. 6 +/- 1.6 days (p < 0.05) and readmission to the hospital was 4% in the diazepam group versus 27% in other group (p < 0.05). There was a significant reduction in nausea in the diazepam group (p < 0.05). A significant reduction in vomiting was observed in both groups. No side effects or congenital neonatal malformations were found in the diazepam group. CONCLUSIONS: Intravenous administration of fluids and vitamins is the standard treatment for women hospitalized for hyperemesis gravidarum. The addition of diazepam to the treatment is effective in reducing nausea and does not have teratogenic effects.

Adult↗
PubMed2000

Effects of diazepam on auditory evoked potentials of rats elicited in a ten-tone paradigm.

The effect of diazepam on sensory gating was studied in rats by measuring diazepam effects on auditory evoked potentials (AEPs) elicited in a ten-tone paradigm. Trains of 10 repetitive tone-pip stimuli were presented. Rats (n = 8) received 4 mg x kg(-1) diazepam subcutaneously or vehicle, counterbalanced over two sessions. Diazepam decreased the amplitude of the middle-latency P30 component and increased the amplitudes of the late-latency N60 and P67 components. The increase in the late-latency components might be due to a diazepam-induced decrease in arousal. Stimulus repetition decreased the amplitudes of the middle-latency N18 and P30 components in both conditions. This suggests that automated neuronal recovery functions underlying sensory gating remain intact with diazepam. In the vehicle condition, the amplitude of the late-latency P67 decreased with stimulus repetition, but not in the diazepam condition. This suggests a diazepam-induced decrease of behaviourally mediated habituation.

Acoustic Stimulation↗
PubMed1992

Comparative study on the behavioral and EEG changes induced by diazepam, buspirone and a novel anxioselective anxiolytic, DN-2327, in the cat.

Behavioral and EEG effects of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4)-dioxa-8-(azas piro-[4.5]dec-8- yl)carbonylmethyl]isoindolin-1-one (DN-2327; 1, 5 and 20 mg/kg p.o.) were compared to those of diazepam (0.2 and 1 mg/kg p.o.) and buspirone (1 and 5 mg/kg p.o.) in freely moving cats. DN-2327 did not affect motor coordination or the relative percentages of the three sleep-wakefulness stages. Diazepam (1 mg/kg) increased wakefulness and non-REM sleep, and buspirone (5 mg/kg) also increased wakefulness and decreased REM sleep. In addition, diazepam (1 mg/kg) caused severe motor disturbance, but buspirone did not. The cortical EEG power density spectra during wakefulness were changed almost dose-dependently by DN-2327 (decreased: 2-7.75 Hz; increased: 20-49.75 Hz), and dose-dependently by diazepam (decreased: 2-7.75 Hz; increased 13-49.75 Hz) and buspirone (decreased: 4-9.75 and 13-19.75 Hz). The effect of DN-2327 on the cortical EEG varied with the sleep-wakefulness stage. The power of the 4- to 7.75-Hz frequency (theta) band of the hippocampal EEG during wakefulness was decreased by diazepam and buspirone but not by DN-2327, while the peak frequency of its spectra was decreased only by diazepam. On the other hand, during non-REM sleep, DN-2327 decreased the power of the theta band as did diazepam. These results indicate that the behavioral and EEG effects of DN-2327 differ completely from those of buspirone and considerably from those of diazepam and that the EEG effect of DN-2327 varies with the sleep-wakefulness stage.

Animals↗
PubMed1981

Alcohol does not enhance diazepam absorption.

A single 5-mg oral dose of diazepam was administered to 6 healthy volunteers on 3 occasions in a randomized 3-way crossover study. Modes of administration were: (A) (control): diazepam with 120 ml of water, preceded 30 min before with 120 ml of water; (B) diazepam with 120 ml water, preceded by 120 ml of a 50:50 vodka:water mixture, and (C) diazepam with 120 ml of the vodka mixture, preceded by 120 ml of water. Peak plasma diazepam levels averaged 166, 140 and 145 ng/ml in trials A, B and C, respectively; the time of peak concentration was 0.71, 2.1 and 1.5 h after the dose, respectively. Differences were not significant. Total areas under the plasma concentration curve were nearly identical (2.7, 2.8 and 2.9 micrograms/ml X h) among the 3 trials, as were values of diazepam elimination half-life (29, 36 and 35 h). The rate and extent of desmethyldiazepam formation also did not differ among trials. Thus, coadministration of diazepam with or shortly after a typical social cocktail tends to slow the rate of diazepam absorption, but does not influence the completeness of absorption or the rate of elimination.

Absorption↗
PubMed1975

The effects of age and liver disease on the disposition and elimination of diazepam in adult man.

This study investigates the separate effects of age and hepatocellular liver disease on the disposition and elimination of diazepam (Valium) in man. The drug was given either by rapid intravenous injection (0.1 mg/kg) or orally (10 mg) to 33 normal volunteers rnaging in age from 15 to 82 yr as well as to 9 individuals with alcoholic cirrhosis, 8 with acute viral hepatitis, and 4 with chronic active hepatitis. In the normal individuals, the terminal plasma half-life of diazepam, (t 1/2 (B)) exhibited a striking age-dependence; at 20 yr the t 1/2 (beta) was about 20 h, but it increased linearly with age to about 90 h at 80 yr. The plasma clearance of diazepam in the majority of the normal subjects was between 20 and 32 ml/min and showed no significant age-dependence. Cigarette smoking did not affect the half-life or the clearance. Additionally, neither the plasma binding (97.4 plus or minus 1.2%, mean plus or minus SD) nor the blood/plasma concentration ratio (0.58 plus or minus 0.16) of diazepam showed any age-related changes (P greater than 0.05). By contrast, analysis of the intravenous data according to a two-compartment open model indicated that both the initial distribution space (V1) and the volume of distribution at steady state [Vd(ss)] of diazepam increased linearly with age (P less than 0.005). The increase in Vd(ss) was secondary to the change in V1. It appears then that the prolongation of t 1/2 (beta) of diazepam with age is primarily dependent on an increase in the initial distribution volume of the drug. The plasma concentration/time course of the metabolite, desmethyldiazepam, was also affected by age. In older individuals, the initial presence and the peak values of desmethyldiazepam were observed later and the metabolite was present in lower concentrations. Despite the profound prolongation of t 1/2 (theta) with age, the constancy of diazepam clearance indicates that drug plasma concentrations will not accumulate any more in the old than the young, and chronic dosage more in the old than the young, and chronic dosage modifications based on pharmacokinetic considerations are unnecessary. Data obtained in patients with liver disease were compared with those found in age-matched control groups. Patients with cirrhosis showed a more than twofold prolongation in the half-life of diazepam (105.6 plus or minus 15.2 vs. 46.6 plus or minus 14.2 h, P less than 0.001).

Administration, Oral↗