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PubMed2003

Phenytoin-diazepam interaction.

OBJECTIVE: To report a case of phenytoin toxicity potentially associated with concurrent diazepam therapy. CASE SUMMARY: A 44-year-old First Nations man presented to the emergency department with headache, nystagmus, diplopia, and ataxia. Apart from a long-standing seizure disorder, his past medical history was unremarkable. The antiepileptic drug regimen of phenytoin, phenobarbital, and lamotrigine had been unchanged for almost 5 months. Total phenytoin serum concentration reported 2 weeks prior to hospital admission was 8 micro g/L. Two days prior to admission, he was prescribed amoxicillin and diazepam; he denied use of nonprescription or herbal medications. The serum phenytoin concentration drawn in the hospital was 37 micro g/mL. Both phenytoin and diazepam were stopped, and the symptoms resolved. His neurologic abnormalities were attributed to phenytoin toxicity caused by an interaction with diazepam. DISCUSSION: The literature documenting a potential interaction between diazepam and phenytoin is conflicting. Case reports and controlled studies have demonstrated both increases and decreases in serum phenytoin concentrations when these agents were administered concomitantly. Phenytoin induces the metabolism of drugs that are substrates of CYP2C, CYP2D, and CYP3A; however, phenytoin is eliminated predominantly by CYP2C9- and CYP2C19-dependent hepatic metabolism. Diazepam is one example of a drug that is extensively metabolized by CYP2C19 and could potentially influence phenytoin elimination by acting as an alternate substrate for this isoenzyme. In our patient, the timing of drug administration, clinical and physical examination findings, and laboratory data suggest that diazepam therapy resulted in phenytoin toxicity. Use of the Naranjo probability scale indicated a probable relationship between the adverse clinical effects observed and phenytoin and diazepam coadministration in this patient. CONCLUSIONS: Phenytoin is a known inducer of drugs metabolized by CYP2C, CYP2D, and CYP3A, but its own metabolism may be altered by drugs influencing CYP2C9 or CYP2C19, such as diazepam. Agents not acting as enzyme inhibitors or inducers, but instead behaving as alternate substrates for enzyme-binding sites, may produce clinically relevant drug interactions through an underrecognized mechanism.

Adult↗

PubMed1999

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

The in utero exposure of hamsters to low doses of diazepam results in impaired host defense against Mycobacterium bovis during adulthood. Delayed developmental immunotoxicity, however, represents a specific situation that might not be general. The present experiment was undertaken to investigate the effects of diazepam on hamster resistance to M. bovis using adult animals. The effects of diazepam treatment on serum cortisol levels were also studied. Adult hamsters (N = 10 for each group) were treated with diazepam (E1 = 1. 0, E2 = 2.0 or E3 = 3.0 mg kg-1 day-1 subcutaneously) or with control solution (C) for 30 days. Seven days after the beginning of the treatment, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with the higher (2.0 and 3.0 mg kg-1 day-1) doses of diazepam exhibited: 1) increased granuloma areas in the liver (C = 1.81 +/- 1.39, E2 = 10.29 +/- 4.64 and E3 = 15.80 +/- 4.82) and lung (C = 0.54 +/- 0.55, E2 = 6.28 +/- 3.85 and E3 = 6.31 +/- 3.56) and 2) increased scores of M. bovis colony-forming units isolated from liver (C = 2.0, E2 = 3.0 and E3 = 3.5), lung (C = 1.0, E2 = 3.0 and E3 = 3.5) and spleen (C = 1.0, E2 = 2.5 and E3 = 4.0). These effects were dose dependent, and were not detected or were less severe in animals treated with the lowest (1.0 mg/kg) dose of diazepam as well as in those of the control group. Furthermore, diazepam treatment (3.0 mg kg-1 day-1 for 30 days) increased (E3 = 71.32 +/- 2.99; N = 10) the serum levels of cortisol compared to control hamsters (C = 22.61 +/- 2.75; N = 10). The present data, that demonstrate an impaired defense against M. bovis in adult hamsters treated with diazepam, were tentatively explained on the basis of a direct and/or indirect action of diazepam on the cytokine network. The effects may be related to stimulation of peripheral benzodiazepine receptor binding sites (PBR) by macrophages and/or lymphocytes, or they may be mediated by PBR stimulation of the adrenals.

Analysis of Variance↗

PubMed1989

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.

Adult↗

PubMed1995

Discriminative stimulus effects of diazepam and buspirone in normal volunteers.

A within-subject design was used to characterize the effects of dose manipulations on discriminative and self-reported effects of oral diazepam and buspirone. Subjects were trained to discriminate diazepam (10 mg) versus placebo (n = 10), or buspirone (10 or 15 mg) versus placebo (n = 9). The compounds were identified to subjects by letter code before discrimination training began. In later sessions, correct identifications at 2 hr after the oral administration of drug earned money. All subjects showed accurate discrimination performance during the test-of-acquisition phase. In a low-dose generalization phase, diazepam and buspirone produced dose-related increases in drug identifications across a four-fold range of doses. In a subsequent low-dose training phase, in which subjects were trained to discriminate progressively lower drug doses, the median lowest discriminable dose of diazepam and buspirone was 2.5 and 7.5 mg, respectively. Dose-response functions for drug identifications were shifted leftward in the low-dose training phase relative to the low-dose generalization phase, suggesting that reinforcement of progressively lower doses enhances drug discriminability. The self-reported effects of diazepam and buspirone were similar (e.g., both drugs increased ratings of drug strength and clumsy/uncoordinated) and different (e.g., diazepam but not buspirone increased ratings of drowsy/sleepy; buspirone but not diazepam increased ratings of tense/nervous). This study demonstrates discriminative and self-reported effects of diazepam and buspirone at doses lower than previously shown to be behaviorally active, and suggests that at commonly used clinical doses, diazepam is relatively more discriminable than buspirone.

Administration, Oral↗

PubMed1983

The effects of chronic diazepam treatment on body weight and food intake in rats.

A series of experiments are reported in all of which the effects of chronic (14-18 days) diazepam treatment on body weight were evaluated under various conditions, and one experiment in which weight gain and daily food intake were monitored simultaneously. The effect of diazepam treatment on body weight was compared to that of vehicle treatment in the following groups: (1) young adult females, (2) pregnant females, (3) shock treated young males (4) nonshocked young males. The effect of diazepam treatment on prenatally diazepam exposed and nonexposed males and females was investigated at seven months of age. Food intake was also measured during chronic diazepam and vehicle treatment. The findings show consistent and reliable differences between diazepam and vehicle treatment. Diazepam treated animals eat less in the long run and gain less weight than vehicle treated controls. Prenatal exposure to diazepam enhances the effect of diazepam treatment in adulthood.

Analysis of Variance↗

PubMed2000

Effects of treatment with amphetamine and diazepam on Mycobacterium bovis-induced infection in hamsters.

Tuberculosis is an example of an infection with an intracellular bacterium in which sensitivity is determined mainly by the host response. Macrophages are the architectural and functional units of the granulomas described in tuberculosis. Treatment with amphetamine (AMPH) and diazepam has been reported to decrease macrophage activity. The present experiment was undertaken to investigate the effects of AMPH and/or diazepam given alone or in combination on hamster resistance to Mycobacterium bovis. The effects of these treatments on serum cortisol levels were also studied. Adult hamsters were treated i.p. with AMPH (group E1 = 1.0 or 2.0 mg/kg/day), with AMPH (group E2 = 1.0 or 2.0 mg/kg/day) plus diazepam (2.0 mg/kg/day), with diazepam (group E3 = 2.0 mg/kg/day), or with control vehicles (1.0 ml/kg/day) for 40 days. Six days after the beginning of the treatments, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with AMPH plus diazepam exhibited: 1) increased weight loss; 2) increased mortality; 3) increased scores of M. bovis colony forming units (CFU) isolated from liver, lung and spleen; 4) increased granuloma areas measured in the liver, lung and spleen. These effects were not induced by AMPH (1.0 or 2.0 mg/kg/day) given alone and were produced by diazepam (2.0 mg/kg/day) treatment per se. Furthermore, AMPH (2.0 mg/kg/day) and diazepam (2.0 mg/kg/day) given alone or in combination for 20 days increased the serum levels of cortisol in relation to control hamsters, with the effect being higher in the animals treated with both drugs. The present data, which demonstrate an impaired defense against M. bovis in hamsters treated with AMPH plus diazepam or with diazepam alone, were tentatively explained on the basis of a direct and/or indirect action of the drugs on macrophage/lymphocyte activity. In the former case, the effects may be related to stimulation of peripheral benzodiazepine receptor sites (PBR) present on macrophages/lymphocytes and/or to a direct effect of ACTH on immune cells, while in the latter they may be mediated by cortisol via PBR and ACTH stimulation of the adrenals.

Amphetamine↗

PubMed2001

Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status.

Diazepam is metabolized by CYP2C19 and CYP3A4 in the liver. CYP2C19 shows genetic polymorphism associated with the poor metabolizer (PM) and extensive metabolizer (EM) phenotypes. The aim of this study was to assess the effect of diltiazem, a CYP3A4 inhibitor, on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Thirteen healthy volunteers (eight EMs and five PMs) were given placebo or diltiazem (200 mg) orally for 3 days before and for 7 days after the oral 2-mg dose of diazepam in a double-blind, randomized, crossover manner. The pharmacokinetics and pharmacodynamics of diazepam were assessed with and without diltiazem. Plasma concentrations and area under the plasma concentration-time curves (AUCs) of diazepam and N-desmethyldiazepam were significantly greater in the PM compared with the EM group during the placebo phase. Diltiazem significantly increased AUC and prolonged elimination t(1/2) of diazepam in both the PM and EM groups. These pharmacokinetic changes, however, caused no significant difference in the pharmacodynamics between the two trial phases. Diltiazem affects the pharmacokinetics of diazepam in the PM and EM groups of CYP2C19. Inhibition of CYP3A4 by a concomitant substrate drug like diltiazem may cause a pharmacokinetic interaction with diazepam irrespective of CYP2C19 genotype status, but whether this interaction would reflect a pharmacodynamic change of diazepam remains unconfirmed by our study.

Adult↗

PubMed2002

Effects of in ovo and acute diazepam treatments on peripheral benzodiazepine receptors and cutaneous basophil hypersensitivity in chickens.

Prenatal diazepam treatment impairs immune responses in mammals, but chicken embryos allow experimental manipulation isolated from maternal influences on embryo development. In ovodiazepam treatment in chickens decreased macrophage spreading and phagocytosis. In the present experiment, we investigated the effects of in ovoand/or acute diazepam treatments on phytohemagglutinin (PHA)-induced cutaneous basophil hypersensitivity (CBH) response in chickens. Forty day-old chickens, treated in ovo with 8 mg diazepam/kg, 2 ml diazepam vehicle/kg, or sham-manipulated. were subsequently treated po with 2 mg diazepam/kg or with diazepam's vehicle 1 h before PHA injection. The existence of an interaction between diazepam treatments was shown. Birds acutely treated with diazepam exhibited an increment in CBH response. In contrast, in ovo diazepam treatment per se did no change animals' response to PHA, but antagonized acute diazepam effects on CBH response. The results occurred through direct and/or indirect action of diazepam on cytokine and/or glucocorticoid hormone production and release. In the former case, the effects might be related to stimulation of peripheral benzodiazepine receptors (PBR) on immune cells, thus changing the cytokine cascade, while in the latter instance they might be mediated through glucocorticoid hormones via PBR stimulation in the adrenal gland cells.

Animals↗

PubMed2005

Diazepam enhances hypericin-induced photocytotoxicity and apoptosis in human glioblastoma cells.

Glioblastoma multiforme (GBM) is neoplasm which is resistant to all currently used treatment modalities including surgery, radiation therapy and chemotherapy. Photodynamic therapy (PDT) has been suggested as a novel therapeutical approach to the treatment of malignant gliomas. Here, we attempted to enhance hypericin-induced photocytotoxicity and apoptosis by diazepam, a non-selective ligand of peripheral benzodiazepine receptors (PBR) which seem to play an important role in apoptosis regulation. For the study, we used U-87 MG and U373 MG glioma cell lines and primary cultures of GBM cells prepared from peroperatively obtained tumor specimens. The patients included 7 histologically confirmed GBMs. Colorimetric MTT assay was employed to study the photocytotoxic effects of hypericin and diazepam. Flow cytometry was used to detect apoptosis and assess the proapoptotic effects of diazepam. We found that hypericin upon photoactivation exerts strong cytotoxic effects against U-87 MG and U373 MG cells as well as primary GBM cell cultures. No cytotoxic effect of hypericin was observed under dark conditions. Diazepam inhibited cell growth in U-87 MG cells and primary cultures whereas proliferation of U373 MG cells remained unaffected. When hypericin was combined with diazepam, photocytotoxicity was increased in U-87 MG cells and primary cultures unlike U373 MG cells. Flow cytometric analysis revealed photoactivated hypericin-induced apoptosis in both cell lines. Apoptosis was significantly enhanced by diazepam in U-87 MG cells. However, no such effect was observed in U373 MG cells. In the present study, we showed that photocytotoxic effect of hypericin in glioma cells can be potentiated by diazepam. This effect is underlied by the ability of diazepam to facilitate hypericin-induced apoptosis. This work provides support to performe clinical studies involving diazepam in the antiglioma treatment regimens as an apoptosis-modulating agent.

Adult↗

PubMed1976

Effect of diazepam on the electroencephalographic pattern and vigilance of unanaesthetized and curarized rats with a chronic cobalt-gelatin focus.

The author studied the effect of diazepam in doses of 1 and 3 mg/kg on rats with a chronic cortical cobalt-gelatin focus and implanted cortical and subcortical electrodes. Focal spike activity localized at the site of the focus and hypersynchronous generalized episodes of spikes (and waves) of 8--9/sec frequency were studied in the electroencephalogram and the main phases of vigilance (waking, telencephalic slow waves/SWS/and REM sleep) after diazepam were evaluated. The effect of diazepam on rats temporarily immobilized with tubocurarine was also evaluated. 1. Focal spike activity during sleep was mildly inhibited by diazepam. If present in the waking state, it was markedly inhibited. 2. The number of episodes diminished significantly after diazepam. The maximum decrease occurred 30--45 minutes after administering diazepam and after that they slowly recovered. 3. Diazepam did not inhibit alteration of the phases of vigilance, but there was an increase in the proportion of telencephalic sleep with large numbers of spidles of 12--14/sec frequency and the incidence of REM phases rose by 250--300%. 4. Diazepam brought no renewal of the episodes which disappeared from the waking EEG recording of rats with a chronic focus temporarily immobilized with tubocurarine. Its administration was followed mostly by sleep activity with spindles. 5. Despite certain effects in common (disappearance of episodes), the action of diazepam differs from that of barbiturates in many respects and is effected by different mechanisms.

Animals↗

PubMed1989

Responses of substantia nigra pars reticulata neurons to benzodiazepine ligands after acute and prolonged diazepam exposure. II. Modulation of firing rate.

We have examined the effects of chronic (3 week) and acute (1 hr) exposure to diazepam on firing rate responses of reticulata neurons to the inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and the benzodiazepine antagonist Ro15-1788. The ability of DMCM and Ro15-1788 to alter firing rate were tested in control, chronic diazepam and acute diazepam-treated rats. In controls, DMCM increased firing rate of reticulata neurons. This effect was reversed by Ro15-1788, which had no effect on firing rate when administered alone. In acute and chronic diazepam-treated groups, low doses of DMCM were less effective in increasing firing than in controls. However, the administration of high doses of DMCM to diazepam-treated animals increased firing rates above the rates observed in control animals after the same compounds. Administration of Ro15-1788 also increased reticulata firing rates above control levels in both acute and chronic diazepam-treated groups. The similarity in reticulata responses after chronic (3 week) and acute (1 hr) diazepam treatments suggests that the altered properties of the benzodiazepine ligands observed after chronic exposure could reflect the presence of diazepam. This may indicate that reticulata neurons themselves do not show changes in sensitivity to benzodiazepine ligands after chronic benzodiazepine exposure. We propose that the altered responses to DMCM and Ro15-1788 in diazepam-treated rats reflect a compensatory change which occurs by 1 hr and maintains reticulata activity at a constant level throughout the period of prolonged exposure to the agonist.

Animals↗

PubMed1989

Animal model of anxiety: effect of acute diazepam treatment in the older adult genetically hypertensive rats of Koletsky type and in the older adult rats of Wistar strain.

The experiments were performed in the older adult (10-14 months of age) normotensive rats of Wistar strain and in the genetically hypertensive rats which developed Koletsky; the experiments were performed in both sexes. The behavior of control and diazepam treated rats were traced in the holeboard and in the elevated plus-maze. In the control animals when compared to the normotensive rats of both sexes show increase in total time of locomotor-exploratory activity in holeboard. In control animals the lowest level of directed exploration was found in the genetically hypertensive males. The control genetically hypertensive males show also the highest aversion towards open space and hight in the elevated plus-maze. Diazepam increases directed exploration in the genetically hypertensive rats of both sexes; directed exploration in the normotensive rats is not influenced by diazepam or this drug caused decrease. Diazepam shows no effect in between-session habituation of directed exploration in the normotensive rats of both sexes; in the genetically hypertensive rats under diazepam treatment instead of between-session habituation of directed exploration there appears in the second session elevation of directed exploration. Diazepam treatment alleviates in the first session aversion towards open space and hight in the elevated plus-maze only in the genetically hypertensive rats of both sexes and in the normotensive males. In the second session statistically significant alleviation of aversion towards open space and hight was attained in both strains of rats, in both sexes and under the both doses of diazepam. Considering the different markers of aging, stress plasma corticosterone and/or diazepam induced hypothermia show tighter age dependence in the genetically hypertensive rats than in the normotensive rats of Wistar strain. On the other hand, the effect of diazepam on aversion towards open space and hight show closer age dependence in the latter type of rats.

Age Factors↗

PubMedDate not supplied

Induction of general anesthesia with diazepam or thiopental: a comparison of the cardiorespiratory effects.

Detailed cardiorespiratory studies were performed in 10 volunteers in whom general anesthesia was induced with thiopental 3 mg/kg and diazepam 0.4 mg/kg.Minimal changes in blood pressure were noted with both agents. Depression of total peripheral resistance lasted in excess of 20 minutes with diazepam but had returned to control levels with thiopental, elevations in cardiac rate and output were most evident and lasted longer with diazepam. In the healthy volunteer induction of anesthesia with diazepam causes alterations in cardiovascular parameters which are more profound than with thiopental. The data presented is in contrast to that obtained when patients with cariovascular disease are studied.With diazepam, considerable individual variation and long recovery times were confirmed.Following extensive clinical use, a detailed study demonstrated minimal cardiovascular depression following intravenous induction of sedation with diazepam, in patients who had prior cardiovascular disease. Subsequent studies suggested that diazepam would be a more suitable alternative for induction of general anesthesia in patients with cardiovascular disease. This was confirmed by Ikram and Rubin. It has been used extensively for sedative techniques in dentistry, and therefore it was logical to extend this concept to the induction of general anesthesia by intravenous diazepam. It was decided to evaluate the use of intravenous diazepam for induction of general anesthesia and to compare the detailed cardiovascular and respiratory effects of this drug with thiopental.

Adult↗

PubMed1986

Pentazocine and codeine: effects on human performance and mood and interactions with diazepam.

Effects of two opioid analgesics on performance and their interactions with diazepam were studied double-blind and cross over in ten healthy students. At two-week intervals the subjects received first a single oral dose of placebo, codeine (100 mg) or pentazocine (75 mg). Then, 1 h 30 min later they were all given diazepam (0.25 mg/kg) orally. Lastly, naloxone (0.4 mg) was injected intravenously at 4 h. In addition to this, the subjects on pentazocine received a second 75 mg dose at 3 h. Codeine and pentazocine alone failed to affect performance in objective tests (body sway, digit symbol substitution, flicker fusion, Maddox wing, nystagmus) recorded at 1 h 30 min. Visual analogue scales showed subjective drug effects: pentazocine made the volunteers talkative, contented, interested and energetic, whilst codeine rendered them mentally slow. 75 mg of pentazocine and 100 mg of codeine produced comparable plasma opiate activity (determined in morphine equivalents) according to radioreceptor bioassay with [3H]-dihydromorphine as a ligand. Impaired performance was clear at the tests done 1.5 and 2.5 h after diazepam. No major interactions were found between opiates and diazepam in objective tests with the exception that nystagmus was stronger after the combined treatment than after diazepam alone. Codeine reduced the absorption of diazepam. Subjectively codeine and pentazocine counteracted the effects of diazepam. The subjects overestimated their performance after opiate + diazepam when compared to diazepam alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Effect of a polyethylene-lined administration set on the availability of diazepam injection.

Delivery of diazepam through a polyethylene-lined i.v. administration set and through a polyvinyl chloride (PVC) set was compared. Diazepam was prepared in concentrations of 50 mg/500 mL and 100 mg/500 mL in 0.9% sodium chloride injection and 5% dextrose injection in glass containers. Diazepam concentrations were measured by high-performance liquid chromatography at 0 through 5 hours in samples collected simultaneously from the glass solution containers and from the distal ends of a PVC administration set and a polyethylene-lined (non-PVC) set. Flow rates of 50 and 100 mL/hr were tested. For the non-PVC sets, diazepam concentration in the infusate was not significantly different from concentration in the glass container at any sampling time. The overall percentage of diazepam recovered was 100.7 +/- 6.8%. For the PVC sets, diazepam concentration in the infusate was less than in the container at all sampling times, and the overall percentage of diazepam recovered was 65.4 +/- 13.3% (significantly different from delivery for the non-PVC sets). Delivery through the non-PVC sets was not affected by flow rate, type of solution, or concentration of diazepam. For infusion periods of up to five hours, delivery of diazepam through polyethylene-lined i.v. administration sets was superior to delivery through polyvinyl chloride sets.

Diazepam↗

PubMed1977

Possible involvement of GABA mechanisms in central cardiovascular and respiratory control. Studies on the interaction between diazepam, picrotoxin and clonidine.

Various doses (0.1-1 mg/kg) of diazepam were given to chloralose anesthetized rats, with both systemic (i.p.) and central injections being tested. Arterial pressure, heart rate, respiration depth and frequency were recorded. Diazepam caused a dose-dependent decrease in the arterial pressure after systemic administration and also decreased it after central administration. However, only intraventricular but not intracisternal injections of diazepam were effective. The hypotensive effect of systemic diazepam was competitively counteracted by pretreatment with picrotoxin, a putative gamma-aminobutyric acid receptor blocking agent. The hypotensive effect of the centrally acting alpha-adrenoreceptor agonist clonidine was not influenced by picrotoxin pretreatment. The effect of diazepam on heart rate was inconsistent. Diazepam caused a reduction of respiratory frequency, which was not counteracted by picrotoxin pretreatment. It is concluded that central gabergic mechanisms are to some extent involved in the hypotensive effect of diazepam, probably at a supramedullary level. The hypotensive effect of a threshold dose of diazepam was blocked by a small dose of clonidine. Likewise, diazepam pretreatment could counteract the hypotension, bradycardia and respiratory frequency reduction caused by a threshold dose of clonidine. These results suggest that gabergic and/or other benzodiazepine-sensitive receptors may interact with alpha-adrenoreceptors in the control of central cardiovascular and respiratory mechanisms.

Aminobutyrates↗

PubMed1984

Effects of diazepam on arterial blood gas concentrations and pH of adult rats acutely and chronically exposed to methadone.

The effects of diazepam alone, and in combination with acute and chronic exposure to methadone, on arterial pH, pCO2 and pO2 in the rat were evaluated. Measurements were made before drug administration and at 15, 30, 60, 120, 180 and 240 min postadministration. Diazepam (20 mg/kg s.c.) did not cause any significant changes in arterial pCO2 or pH. However, it did cause a significant increase in arterial pO2 tension (P less than or equal to .05). The magnitude of this effect was essentially the same after acute and chronic diazepam treatment. The increase in arterial pO2 tension was attributed to a decrease in tissue uptake of oxygen associated with the decrease in body temperature that occurred after diazepam treatment. Acute and, to a far lesser extent, chronic administration of methadone (5 mg/kg/day i.p.) caused significant decreases in arterial pH and pO2 and increases in pCO2 (P less than or equal to .05). When given in combination with methadone, diazepam potentiated markedly the respiratory depressant effects of methadone. The most severe respiratory depression occurred when both drugs were used together acutely. The effects of the acute diazepam-chronic methadone treatment were 100 to 200% greater than those that occurred with the chronic diazepam-chronic methadone treatment, indicating the development of a tolerance to the potentiating ability of diazepam. These results show that there is a real potential for severe respiratory depression when these drugs, methadone and diazepam, are used concurrently, especially for the first time.

Animals↗

PubMed1984

Comparison of diazepam and oxazepam: preference, liking and extent of abuse.

In a residential hospital research ward setting, the effects of and preference for placebo, oxazepam (480 mg) and diazepam (40, 80 and 160 mg) were studied in human volunteers with histories of sedative drug abuse. Doses p.o. were administered every 3rd day under double-blind conditions. After an initial exposure to the letter-coded test drugs, a series of choice days was scheduled on which subjects chose between two available drug alternatives. Compared with oxazepam, diazepam produced greater liking (area under the time-action curve), peak liking and euphoria and was judged to be of greater monetary street value. Diazepam was categorized as producing barbiturate-like subjective effects more frequently than was oxazepam (54 vs. 21%), whereas oxazepam was identified as placebo more often than diazepam (32 vs. 4%). Diazepam was associated with a more rapid onset of effect than was oxazepam, and this rapid onset was repeatedly cited by subjects in poststudy written comments as being a desirable feature of the drug effect. In choice tests, 80 and 160 mg of diazepam were preferred to 480 mg of oxazepam on 62.5 and 91.7% of the choice tests, respectively. In choice tests between placebo and drug, placebo was never preferred to diazepam; however, placebo was preferred to oxazepam on 21.4% of choice tests. Overall, these results extend previous experimental observations suggesting that diazepam has a higher abuse liability than oxazepam. The results are also compatible with an analysis of epidemiological data showing that diazepam abuse uniformly exceeds oxazepam abuse on seven epidemiological measures of drug abuse.

Adult↗