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PubMed1989

Models of hepatic elimination: implications from studies of the simultaneous elimination of taurocholate and diazepam by isolated rat liver under varying conditions of binding.

Various kinetic models have been developed to describe the elimination of substances by the liver, but there is no agreement about which model is the most appropriate, as experimental evaluation is incomplete and results conflict. We have shown previously that hepatic elimination of taurocholate is best described by models that embody a high degree of sinusoidal heterogeneity or mixing, whereas another study showed that elimination of diazepam is best described by models that embody a low degree of sinusoidal heterogeneity or mixing. To investigate this discrepancy we examined, in the isolated perfused rat liver, the simultaneous elimination of taurocholate and diazepam. The effect on hepatic availability of varying unbound fraction (fu) in a single pass, steady-state system was studied in six experiments for taurocholate (fu, 0.066-0.966) and diazepam (fu, 0.051-0.675) by varying perfusate albumin concentration (0-60 g l-1). As before, elimination of taurocholate was best described by models that embody a high degree of sinusoidal heterogeneity or mixing (i.e., venous equilibrium model, dispersion model with dispersion number = infinity). Diazepam elimination was best described by models that embody a low degree of sinusoidal heterogeneity or mixing (undistributed sinusoidal model, dispersion model with low dispersion number = 1.04). A third model, a distributed model incorporating heterogeneity of sinusoidal blood flows and intrinsic clearances, fitted the data for both taurocholate and diazepam. The fitted coefficients of variation of both flow and intrinsic clearance among the sinusoids were large for taurocholate (176 and 164, respectively), but for diazepam blood flow was large (200) whereas that for intrinsic clearance was small (0.807).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Ca2+-agonistic effects of diazepam, a benzodiazepine 1-4 derivative, on isolated mouse and guinea pig left atria.

In normal Krebs solution, diazepam (1.75X10(-4) M) increased the action potential duration in a reversible form and caused a positive inotropic effect on mouse auricular muscle (4). 2.) Further studies on diazepam action on electrical and mechanical activity of left auricular muscle from mouse and guinea pig, in preparations electrically driven, showed that diazepam induces an increase in action potential duration measured at 20% repolarization, a decrease in the rate of spike depolarization, and modifies the conduction velocity of the action potential. 3.) Diazepam produced in preparation with spontaneous activity, positive chronotropic and inotropic effects, and positive inotropic effect in electrically driven preparations. 4.) The change in action potential duration induced by diazepam on mouse preparations was higher than on guinea pig preparations, ca.X3. 5.) These findings support that diazepam action may be due to an increase in the inward calcium current and a reduction in the inward sodium current.

Animals↗
PubMed1986

Behavioral effects of zopiclone, CL 218,872 and diazepam in squirrel monkeys: antagonism by Ro 15-1788 and CGS 8216.

The effects of zopiclone, CL 218,872 and diazepam were compared in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. Dose-response curves were determined for each drug by administering cumulative doses i.v. during timeout periods that preceded sequential components of the FI schedule. Low and intermediate doses of zopiclone (0.03-1.0 mg/kg), CL 218,872 (0.3-3.0 mg/kg) or diazepam (0.1-1.0 mg/kg) produced dose-related increases in the rate of FI responding. The highest doses of diazepam (10.0 mg/kg) and CL 218,872 (30.0 mg/kg), but not of zopiclone (30.0 mg/kg), decreased FI responding markedly. Doses of zopiclone, CL 218,872 and diazepam that were effective in increasing FI responding were similar to the doses reported previously to increase suppressed (punished) responding in squirrel monkeys. Pretreatment with the benzodiazepine antagonists Ro 15-1788 or CGS 8216 (1.0 or 3.0 mg/kg) reduced or eliminated the increases in FI responding produced normally by intermediate doses of zopiclone, CL 218,872 or diazepam, suggesting that the rate-increasing effects of the three agonists reflect similar actions at benzodiazepine recognition sites. In contrast, Ro 15-1788 and CGS 8216 were less effective or ineffective in attenuating the marked decreases in FI responding produced by the highest doses of CL 218,872 or diazepam, suggesting that the rate-decreasing effects of these agonists are mediated differently from their rate-increasing effects.

Animals↗
PubMed1987

A comparison of buspirone, diazepam, and placebo in patients with chronic anxiety states.

Buspirone is an antianxiety compound that has been extensively evaluated in clinical trials: it has proved superior to placebo and comparable to diazepam in the treatment of patients with generalized anxiety disorder. In this study, 33 outpatients with generalized anxiety disorder were entered into a crossover study of 3 weeks each of placebo, buspirone 10 to 30 mg daily, and diazepam 10 to 30 mg daily. Psychiatrist and patient ratings were made, together with psychological tests and EEG and skin conductance measures before and after each treatment. Of the nine dropouts, six were on buspirone at the time of dropout. For the remaining 24 patients, the mean daily doses attained of buspirone and diazepam were both 20 mg. On most clinical ratings diazepam was superior to buspirone and placebo, which did not differ. Diazepam produced minor psychomotor changes and the expected major effects on the EEG. Buspirone was without effect. Side effects on buspirone were mainly nausea and giddiness and on diazepam, drowsiness. The lack of efficacy of buspirone is discussed in terms of the previous benzodiazepine exposure--23/24 patients had had previous exposure and only 10 were able to tolerate a pretrial placebo washout period. The implications are considerable for the introduction of any new antianxiety agent not cross-tolerant with the benzodiazepines into a chronically anxious group of patients with previous long-term benzodiazepine therapy.

Adult↗
PubMedDate not supplied

Diazepam metabolism in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man.

Diazepam metabolism has been investigated in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man. The metabolite profile obtained by HPLC analysis of the culture medium indicated that substantial differences exist corresponding to known species differences in the metabolite profile of diazepam in vivo. These differences were attributed to a combination of the rate at which a metabolite was formed and the rate at which it is removed from the medium by further metabolism. The intrinsic clearance of nordiazepam in hepatocytes from each of the species exhibited the most marked species variation (rat much greater than guinea pig greater than rabbit greater than human greater than dog). Species that exhibited a high intrinsic clearance for nordiazepam were also those species that exhibited significant hydroxylation at the 4'-site of the molecule. The disappearance of diazepam was rapid in rat, dog, and guinea pig hepatocytes, but slow in human hepatocytes. Moreover, rat and human hepatocytes exhibited different saturability of diazepam clearance with respect to diazepam concentration accounting, at least in part, for the different rates of diazepam metabolism in the different species. These results support the value of hepatocytes in drug metabolism studies and especially in studies of species differences in metabolism.

Adult↗
PubMed1988

Comparative neurologic effects of diazepam and suriclone, a cyclopyrrolone anxiolytic.

Suriclone selectively displaces benzodiazepines from their binding sites but is structurally unrelated to benzodiazepines. Neurologic effects of suriclone were compared to those of diazepam in 54 subjects in a sequential, double-blind, single dose, randomized study (placebo; diazepam 10 mg; suriclone 0.2, 0.4, 0.6, or 0.8 mg). Data were collected on-line by microcomputer. Suriclone 0.2 mg did not differ from placebo. Suriclone 0.4 mg and 0.6 mg did not differ from diazepam 10 mg. Suriclone 0.8 mg caused significantly more decrement than diazepam 10 mg (p less than 0.05) in manual tracking, force platform stability, and Heath rail walking and in total severity of symptoms. Suriclone 0.8 mg caused nausea (p = 0.02), clumsiness (p = 0.02), and loss of balance (p = 0.01) more frequently than diazepam 10 mg. Suriclone 0.8 mg produced symptoms and signs qualitatively and quantitatively different from diazepam 10 mg, such as vomiting, unusual ocular movement effects, and difficulty walking. Possibly the differences in CNS drug binding for anxiolytics are associated with clinical differences in toxicity.

Adult↗
PubMed1985

[Influence of diazepam premedication on upper digestive fiberscopy. 81 cases].

Upper gastrointestinal endoscopy is routinely used to follow up patients with digestive disease. The influence of premedication with diazepam on the procedure and on patients' acceptance of a second endoscopy was evaluated in a double-blind trial conducted on 81 patients randomized to 3 types of intravenous premedication: placebo (group A, 29 patients), diazepam 5 mg (group B, 27 patients) and diazepam 10 mg (group C, 25 patients). Endoscopy was performed under unfavourable conditions (refusal or agitation) in 12, 4 and 1 patients respectively of groups A, B and C (P less than 0.02). Out of 65 patients questioned one month later, 1 (group A) sternly refused a second endoscopy, 10 accepted unreservedly (O in group A, 4 in group B, 6 in group C; P less than 0.05 between A and C) and 54 accepted reluctantly. To find out whether diazepam was beneficial by impairing memory, a memory score on duration of the procedure was established; there were no significant differences between the three groups (P less than 0.001), but they did not correlate with the patients' acceptance of a second endoscopy. It is concluded that premedication with diazepam 10 mg i.v. makes upper gastrointestinal endoscopy easier to perform and facilitates acceptance of a repeat endoscopy 1 month later. This effect is probably independent of the impairment in memory induced by diazepam.

Diazepam↗
PubMed1986

Diazepam potentiates GABA-contraction in guinea-pig ileum.

Both GABA-receptors and benzodiazepine receptors have recently been described in the ileum. In this work we tested whether an interaction between diazepam and GABA-A- or GABA-B-mediated effects took place in guinea-pig ileum longitudinal muscle. We found that diazepam dose-dependently (10(-9) M-10(-6) M) potentiates the contractions caused by the activation of GABA-A receptor while it is ineffective at the same doses on GABA-B- mediated effects (relaxation and inhibition of twitch response). The drug "per se" does not affect the ileum. Diazepam potentiation is specific since this drug does not potentiate contractions caused by acetylcholine (10(-8) M), 5-HT (10(-7) M), histamine (10(-7) M), and electrical stimulation. Diazepam potentiating effect was not evident in the presence of bicuculline (10(-5) M) or hyoscine (2 X 10(-7) M). Ro 15-1788 (10(-5)M) and beta CCE (10(-5)M) antagonized diazepam potentiation of GABA contraction, while PK 11195 (10(-5) M) was ineffective. We conclude that diazepam modulates the effects evoked by stimulation of peripheral GABA-A receptors, while it is ineffective on GABA-B mediated effects.

Animals↗
PubMed1986

Effects of diazepam on pancreatic exocrine secretion in the dog.

The effects of diazepam on pancreatic exocrine secretion were investigated in the vascularly isolated and self-hemoperfused dog pancreas under constant perfusion pressure of 100 mmHg. Close-arterial injections (i.a.) of diazepam (0.3-3.0 mg) caused dose-dependent increases in the secretion of pancreatic juice and in the rate of perfusion blood flow. Protein and bicarbonate concentrations of the pancreatic juice stimulated by 3.0 mg of diazepam were significantly higher than those of the resting pancreatic juice. The secretory activity of 1.0 mg (i.a.) of diazepam was comparable to that of 0.05 units (i.a.) of secretin. These secretory and vascular responses to diazepam were not modified by pretreatments with atropine, sulpiride, cimetidine, theophylline and Ro 15-1788. These results suggest that large doses of diazepam act directly on both acinar and ductular cells of the pancreas and induce protein and bicarbonate secretions.

Animals↗
PubMed1986

CGS 8216: agonist and diazepam-antagonist effects in rodents.

CGS 8216, a pyrazoloquinolinone benzodiazepine receptor ligand, was administered alone and concomitantly with diazepam in order to assess its agonist and diazepam-antagonist properties on several behaviors in rodents. In mice, CGS 8216 (i.p.) potentiated the convulsant effects of pentylenetetrazole. Moreover, doses of 1.0 to 10 mg/kg of CGS 8216 produced dose-related antagonism of the anticonvulsant effects of diazepam. In rats, CGS 8216 (0.3-3.0 mg/kg) was without effect on the Rotarod, but produced dose-related, nonparallel shifts to the right in the diazepam dose-effect curve. Also in rats, behavior was maintained under a multiple schedule where in one component every 20th response resulted in water presentation (unpunished component) and in a second component every 20th response resulted in both footshock and water presentation (punished component). CGS 8216 produced dose-related decreases in response rates in both components, but was approximately 10-fold more potent in decreasing rates of punished responding. These effects were blocked by the benzodiazepine antagonist Ro 15-1788 (30 mg/kg i.p.). Increasing doses of diazepam (0.1-10 mg/kg p.o.) first increased and then decreased rates of punished responding but only decreased rates of unpunished responding. CGS 8216 produced a dose-related antagonism of the rate-increasing, but had little effect on the rate-decreasing, effects of diazepam. In another group of rats, behavior was maintained under a multiple fixed interval 5-min fixed ratio 20-response schedule of water presentation. CGS 8216 produced a dose-related decrease in response rates in both components, but these effects were not blocked by Ro 15-1788 (30 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of diazepam, ethanol and Ro 15-1788 on ultrasonic vocalization, locomotor activity and body righting in the neonatal rat.

It has been suggested that ethanol, besides its stimulating, sedative and ataxic effects, also exerts anxiolytic effects similarly to diazepam. In the present study we tested this hypothesis on ultrasonic distress crying in neonatal rats separated from mother and litter-mates. The results showed that both ethanol and diazepam reduced crying in a dose-dependent manner and at doses not affecting the level of motor activity. It was found that the effects of diazepam, but not that of ethanol, was antagonized by the specific benzodiazepine-receptor-antagonist Ro 15-1788. The effects of ethanol were antagonized by the GABA-ergic antagonist picrotoxin. Assessing the sedative/ataxic effects of ethanol and diazepam by the surface body righting response, it was found that the effect of diazepam, but not of ethanol, was antagonized by Ro 15-1788. The results support the hypothesis that ethanol exerts similar anxiolytic actions as diazepam, but that the effects are mediated by different mechanisms.

Animals↗
PubMed1988

Does diazepam really reduce the cardiotoxic effects of intravenous bupivacaine?

The effect of diazepam on the cardiovascular toxicity of bupivacaine was investigated in a rat model. Under chloral hydrate (400 mg/kg intraperitoneal) anesthesia, unilateral femoral venous and bilateral femoral arterial cannulae were placed for administration of drugs, for blood sampling, and for continuous qualitative monitoring of arterial blood pressure. Lead II ECG was continuously recorded and a tracheostomy performed to increase FIO2 by use of a "T-piece." Four groups of 24 to 36 rats each were studied. All rats received IV bupivacaine 2 mg/kg, within 10 seconds. Group I, the control group, received only bupivacaine. Groups II and III received IV diazepam 0.2 mg/kg, or diazepam vehicle in an equivalent volume, respectively. Five minutes after this pretreatment, groups II and III received IV bupivacaine 2 mg/kg. Group IV was given diazepam, 0.2 mg/kg, 30 seconds after injection of 2 mg/kg bupivacaine. A marked respiratory and metabolic acidosis occurred in all rats but was significantly worse in groups II and III. No rat in the study became hypoxemic. Serious arrhythmias (ventricular or supraventricular tachycardia) were noted in all groups, but the incidence was significantly higher in the group of rats given diazepam pretreatment than in the other three groups. It is concluded that IV diazepam 0.2 mg/kg given 5 minutes before administration of IV bupivacaine 2 mg/kg increases the incidence of serious cardiac arrhythmias. Second, this increase is not solely due to increased acidosis, because the rats receiving the vehicle (group III) developed equivalent acidosis but did not develop increased arrhythmias.

Acidosis, Respiratory↗
PubMed1977

Rapid determination of diazepam and nordiazepam in plasma by electron capture gas--liquid chromatography. Application in clinical pharmacokinetic studies.

A rapid method was developed for the determination of diazepam and nordiazepam (N-desmethyldiazepam) in human plasma using electron capture gas--liquid chromatography (GLC--ECE). The concentration of diazepam and nordiazepam is determined using 0.5 ml of plasma extracted with 1.0 ml of benzene containing 25 ng/ml of methylnitrazepam as the internal standard. The benzene extract is removed and an aliquot is subjected to automated GLC-ECD analysis. The method has a sensitivity limit of 5 ng diazepam and 10ng nordiazepam per milliliter of plasma. The method was used to determine the plasma levels in man following the first 5-mg diazepam dose, as well as during chronic oral administration of 5 mg diazepam three times daily and 15 mg diazepam once a day.

Autoanalysis↗
PubMed1988

Effects of tizanidine in healthy volunteers: double-blind study compared with diazepam and a placebo.

Since an experiment in monkeys showed that tizanidine (DS 103-282), a centrally-acting muscle relaxant, has a certain amount of reinforcing property, a double-blind comparative study using questionnaires was carried out in 12 healthy volunteers to investigate the subjective effects of the drug as a measure of its psychic dependence potential using diazepam and a placebo. The dosages of tizanidine were 3 mg and 6 mg and that of diazepam was 10 mg. Neither the maximal clinical dosage of tizanidine (3 mg) nor twice that dosage (6 mg) induced any marked somatic or psychic symptoms compared with the placebo. On the other hand, diazepam 10 mg induced symptoms at a significantly higher incidence than the placebo and tizanidine; i.e., many of those given diazepam mentioned experiencing such symptoms of central nervous system depression as drowsiness and absent-mindedness. With diazepam the volunteers gave positive answers to some items which are regarded as direct parameters of psychic dependence; e.g., one noted that the drug effects were "desirable", two indicated a "euphoric feeling", and five noted a "drunken feeling". Influence on tapping, blood pressure, etc., were observed in the tizanidine 6 mg group in the same extent as in the diazepam group. The blood concentration of tizanidine 6 mg was about four times as high as tizanidine 3 mg. These results indicate that tizanidine is very unlikely to have psychic-dependence potential because of a lack of observable subjective effects and thus, it was concluded that there is little possibility of the drug being abused.

Adult↗
PubMed1986

Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam.

The pharmacokinetic and dynamic interactions of caffeine and diazepam after single doses were investigated in six young healthy adults. Subjects received 6 mg/kg of caffeine, 0.3 mg/kg of diazepam, and their combination at 2-week intervals according to a Latin square design and a double-blind procedure. Subjects had blood samples withdrawn at 0, 5, 10, 20, 30, 45, 60 minutes and every 30 minutes thereafter until 210 minutes after treatment. A battery of behavioral tests were administered before treatment and after each blood sampling, starting with the 20-minute period. The coadministration of caffeine with diazepam resulted in a 22% reduction in diazepam plasma levels. Caffeine produced hand tremors and diazepam produced sedation and impaired memory and cognition. The two drugs did not antagonize the effects of each other except in the symbol cancellation task. There were significant correlations between the caffeine and diazepam plasma levels and performance on several tasks and evidence for the development of acute tolerance to both drugs.

Adolescent↗
PubMedDate not supplied

[Effect of diazepam on somatosensory evoked potentials].

Somatosensory evoked potentials (SEP) were recorded in 15 patients with extrapyramidal disturbances after intravenous administration of 10 mg of diazepam (Relanium, Polfa). Cortical SEP were recorded before and after operations and thalamic SEP were recorded during stereotaxic interventions on thalamic nuclei VL and Vim. The results demonstrated that diazepam had a significant positive influence on the recording of SEP, eliminating muscular artifacts caused by increased muscular tonus and extrapyramidal tremor. Diazepam had no evident effect on the SEP and caused no changes of the short-latency specific cortical SEP. This effect was, however, evident on the later components of the SEP and it seemed to affect mainly the N63 wave whose amplitude was always reduced or absent. In the postoperative investigations the cortical SEP in the hemisphere operated on (contralateral to the site of stimulation) were reduced in the phase of short-latency components. In the ipsilateral hemisphere the cortical SEP remained similar to the normal ones, and after diazepam their amplitude was markedly reduced. Intraoperatively recorded thalamic SEP showed after diazepam a considerable decrease of the amplitude of all components, sometimes the curve was completely flat, including the specific phase of the potential. On the other hand, diazepam failed to extinguish cortical SEP which showed even a greater amplitude of short-latency and long-latency components than in the records obtained without this drug, with the exception of disappearing N63 component.

Adult↗
PubMed1986

Formulation and stability of diazepam suspension compounded from tablets.

The stability of diazepam in an extemporaneous suspension compounded from tablets was studied. A diazepam 1 mg/mL suspension was prepared by levigating diazepam 10-mg tablets with ethanol and propylene glycol and incorporating them into a suspension vehicle containing magnesium aluminum silicate and carboxymethylcellulose sodium with flavoring and sweetening agents. Samples of the suspension were stored in amber glass bottles at 5, 22, and 40 degrees C. At various times during the 60-day study period, samples were inspected visually for signs of caking or color change and evaluated for ease of pouring and redispersion. Also at those times, the concentration of diazepam in each sample was determined by a stability-indicating, high-performance liquid chromatography procedure. The concentration of diazepam in each sample was at least 90% of the initial concentration throughout the 60-day storage period. All samples remained homogeneous and showed no signs of caking or settling. A diazepam suspension compounded from tablets was found to be pharmaceutically acceptable and easily pourable and redispersible. The suspension is stable for at least 60 days at room or refrigerated temperature.

Chromatography, High Pressure Liquid↗
PubMed1986

Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials.

Effects of buspirone, 10 and 20 mg, and diazepam, 10 mg, on skilled performance and evoked responses, as well as their interactions with 0.8 g/kg of alcohol were investigated in 24 healthy men. Alcohol, 0.8 g/kg, caused the greatest performance impairment, followed closely by diazepam. Both doses of buspirone had lesser effects. Buspirone had primarily sedative effects which were short lasting, whereas diazepam impaired tracking and body balance in addition to being sedative. Both anxiolytics showed only slight additive interactions with the present dose of alcohol. A strong drug effect and a lesser but significant alcohol and a drug/alcohol interaction effect were seen on evoked potentials. Diazepam effects on evoked potentials were similar to alcohol, whereas buspirone in some instances appeared to reverse the alcohol effect. Pharmacokinetics of buspirone and diazepam were not significantly affected by concomitant administration of alcohol. The psychomotor side effect profile of a single anxiolytic dose of buspirone is preferable to a single 10-mg dose of diazepam.

Adult↗