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PubMed1996

Effect of diazepam sedation on arterial oxygen saturation during esophagogastroduodenoscopy: a placebo-controlled study.

OBJECTIVE: To determine the effect of sedation using diazepam on hemoglobin oxygen saturation (SpO2) in patients undergoing esophagogastroduodenoscopy (EGD). METHOD: 100 consecutive patients scheduled for EGD were randomly allocated to receive 0.03 mL/Kg of either diazepam (5 mg/mL solution) or normal saline intravenously after topical oropharyngeal anesthesia immediately before the procedure. SpO2 was continuously monitored throughout the procedure by an anesthetist who was unaware of the drug received. RESULTS: Fall in SpO2 exceeding 4% was noted in 78% of patients in the diazepam group and in 38% of patients in the placebo group (p < 0.001). Fall in SpO2 to suboptimal level (89%) was seen in 20% of patients in the diazepam group and in 10% patients in the placebo group (p < 0.001). The duration of suboptimal SpO2 was similar (means +/- SD being 2.47 +/- 0.10 min in diazepam group and 2.86 +/- 0.32 min in placebo group). CONCLUSION: Intravenous diazepam administration before EGD produces a significant fall in SpO2 during the procedure, and so should be avoided; continuous monitoring of SpO2 should be done during EGD.

Adult↗
PubMed1996

Effects of high doses of diazepam on carrageenin-induced paw edema in rats.

Benzodiazepine (BDZ) receptor sites play a relevant role in immune/inflammatory reactions. Acute BDZ treatments were shown not only to suppress cell proliferation in rat thymus but also to decrease TNF-alpha, IL-1 and IL-6 release from adult mouse macrophages. In the present investigation the effects of acute (10.0 and 20.0 mg/kg) and long-term (10.0 mg kg-1 day-1, for 21 days) diazepam treatment on carrageenin-induced paw edema were studied in rats. The results showed that acute treatment with high doses of diazepam decreased paw edema volume in a dose-dependent manner, and this effect was observed as early as 1 h after the administration of the 20.0 mg/kg dose and continued until the last measurement was performed (8 h). In contrast, long-term diazepam administration did not modify the phlogistic-induced edema. Taken together, these data show that 1) acute diazepam treatment with high doses decreases the volume of the acute inflammatory paw edema developed by the organism as a response to carrageenin-induced injury, and 2) long-term diazepam treatment induces tolerance to this effect. These results are discussed in the light of a possible effect of diazepam on the components of the rat cellular and humoral immune/inflammatory reaction such as T lymphocytes and/or interleukins.

Animals↗
PubMed1997

[Efficacy of rectal diazepam suppository in the prophylaxis of febrile seizures: comparison with rectal chloral hydrate suppository].

We evaluated the efficacy of diazepam and chloral hydrate given rectally for the prophylaxis of recurrence of febrile seizure. The dose were 0.4 mg/kg for diazepam and 250 mg (for children younger than 3 years old) or 500 mg (for over 3 years old) for chloral hydrate. Another dose was given after an interval of 8 hours if body temperature continued to exceed 38.0 degrees C. Among the 452 patients with febrile seizures who visited our hospital from Jan. 1993 to Jun. 1995, 113 were studied who had at least one febrile episode in the follow-up period that extended over 6 months. These patients were divided into two groups: Group D (72 patients given diazepam) and Group C (41 patients given chloral hydrate). In group D and C, the numbers of febrile episodes were 238 and 167, and those of recurrent seizures 8 (3.8%) and 29 (20.4%), respectively. The recurrences rate was significantly higher in the latter group (p < 0.005). There was no statistical difference as to the mean dosage of diazepam or chloral hydrate between the patients with and without recurrence. The numbers of patients with seizure recurrence were 8 (11.1%) in group D and 12 (29.3%) in group C, being significantly larger in the latter (p < 0.005). Diazepam produced more adverse effects than chloral hydrate did. Thus diazepam suppositories for the prevention of recurrence of febrile seizures were more effective than chloral hydrate suppositories.

Child↗
PubMed1997

Age-related changes in the pharmacokinetic disposition of diazepam in foals.

OBJECTIVE: To evaluate changes in the pharmacokinetic disposition of diazepam in foals from 4 to 84 days of age. SAMPLE POPULATION: 4 male and 2 female full-term mixed-breed foals. PROCEDURE: Diazepam terminal half-life, volume of distribution, clearance, free fraction, unbound volume of distribution, free clearance, peak desmethyldiazepam concentration, and area under the desmethyldiazepam concentration-time curve were determined after i.v. administration of 0.25 mg of diazepam/kg of body weight to foals at 4, 21, 42, and 84 days of age. RESULTS: Disposition of diazepam was best described using a two-compartment model. Clearance and free fraction values (mean +/- SEM) determined at 4 days (5.06 +/- 0.79 and 51 +/- 8 ml/kg/min, respectively) were significantly less than those obtained at 21 (8.64 +/- 0.95 and 87 +/- 11 ml/kg/min), 42 (7.31 +/- 0.82 and 83 +/- 10 ml/kg/min), and 84 (8.41 +/- 0.56 and 100 +/- 12 ml/kg/ min) days. Volume of distribution and unbound volume of distribution values determined at 4 days (1.57 +/- 0.11 and 16.0 +/- 1.7 L/kg, respectively) were significantly less than those found at 21 (2.66 +/- 0.33 and 26.8 +/- 3.9 L/kg), 42 (3.00 +/- 0.42 and 33.9 +/- 5.0 L/kg), and 84 (2.55 +/- 0.35 and 30.2 +/- 5.3 L/kg) days. Peak plasma desmethyldiazepam concentration obtained at 4 days (22.7 +/- 2.4 ng/ml) was significantly lower than that obtained at 21 (36.1 +/- 4.5 ng/ml), 42 (38.3 +/- 4.8 ng/ml), and 84 (34.6 +/- 2.1 ng/ml) days. CONCLUSIONS: Factors likely to affect the pharmacokinetic disposition of diazepam in foals, such as body composition and hepatic enzyme activity, are in transition during the first 21 days of life. These have opposing effects on diazepam clearance and volume of distribution so that terminal half-life remains unchanged. However, clearance determines whether diazepam will accumulate with repeated doses, and care should be taken when administering repeated doses to foals < 21 days old.

Adjuvants, Anesthesia↗
PubMed1998

[Effect of diazepam on delayed nausea and vomiting caused by anticancer agents].

We conducted an evaluation of the usefulness of antiemetics (5-Hydroxy-tryptamine 3 receptor antagonism, 5HT3RA) combined with diazepam for delayed nausea and vomiting due to anticancer agents in 17 patients with various malignancies (such as lung Ca, breast Ca, esophagus Ca, gastric Ca, colon Ca, and non Hodgkin's disease) for whom chemotherapy was performed with different regimens in the Dept. of Oncologic Chemotherapy, People's Hospital, Beijing Medical University. Antiemetics (5HT3RA) combined with diazepam were given only to cases that had symptoms of nausea and vomiting induced by anticancer agents in the 1st course and invalidity with antiemetics (5HT3RA) alone in this study. Antiemetic (5HT3RA) agents + Dexamethasone were dosed before chemotherapy and also diazepam 5 mg orally after 24 hours (namely, when nausea was observed). Nausea was reduced and vomiting decreased after the antiemetic treatment with 5HT3RA + Dexamethasone and diazepam. These results indicated that 5HT3RA and diazepam combination therapies were more effective than 5HT3 RA + Dexamethasone alone for delayed nausea and vomiting. Further, the antiemetics had characters that a short adminiter time, few times and a take not over dose. The only side effect related to this antiemetic therapy was light somnolence. Antiemetics combined with diazepam might be a useful therapy against delayed nausea and vomiting induced by anticancer agents.

Adult↗
PubMed1995

Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site.

Benzodiazepines modulate gamma-aminobutyric acid (GABA)-evoked chloride currents through a specific binding site at the GABAA receptor-chloride channel complex. The heterogeneity of diazepam-sensitive benzodiazepine binding sites (type I and type II) has been identified by pharmacological approaches both with native receptors and recombinant receptors coexpressing alpha, beta and gamma subunits. In addition, two distinguishable diazepam-insensitive benzodiazepine sites are found, spatially distributed between cerebral cortical and cerebellar regions. Coexpression of alpha 6 with beta 2 and gamma 2L subunits creates a pharmacologically similar benzodiazepine receptor to the diazepam-insensitive site observed in cerebellum, however, there is no evidence regarding the possible subunit combination forming the DI site in cerebral tissues. Here we report the cloning of the human alpha 4 cDNA and its pharmacology by coexpression of this alpha 4 subunit with beta 2 and gamma 2L subunits. This recombinant receptor complex showed a high affinity for the previously described benzodiazepine partial agonist bretazenill, the pyrazoloquinoline compounds CGS-9895 and CGS-9896, as well as the inverse agonists DMCM (methyl 6,7-dimethoxy 4-ethyl-beta-carboline-3-carboxylate) and Ro15-4513 as determined by [3H]Ro15-4513 binding. However, it is insensitive to the benzodiazepine type I selective compounds CL218.872 (3-methyl-6-[3-(trifluoromethyl)[phenyl]-1,2,4-triazolo[4.3-b]pyridazine ) and zolpidem as well as the benzodiazepine full agonists diazepam, halazolam and midazolam. In addition, the benzodiazepine receptor ligands DMCM, beta-CCE (beta-carboline-3-carboxylate ethyl ester), Beta-CCM (beta-carboline-3-carboxylate methyl ester), FG-7142, CGS-9895 and CGS-9896 showed 7 to 10 times higher affinity for alpha 4 beta 2 gamma 2L. The pharmacology of the alpha 4 beta 2 gamma 2L receptor complex appears to resemble those of the diazepam-insensitive site found in the cerebral cortex. Our study thus suggests that this subpopulation of diazepam-insensitive GABAA receptors may be composed of alpha 4 beta 2 gamma 2L subunits.

Amino Acid Sequence↗
PubMed1983

Differential effects of diazepam and pentobarbital on mood and behavior.

The effects of administering moderately high doses of diazepam and pentobarbital sodium for five consecutive days to subjects with histories of sedative drug abuse were examined. The two drugs produced similar dose-related effects on psychomotor performance, daytime sleeping, and ratings of magnitude of drug effects. Diazepam, but not pentobarbital, produced dose-related decreases in staff ratings of subjects' mood and social interactions and increases in staff ratings of subjects' hostility, complaining, and unusual behavior. During the placebo washout periods that followed drug administration. diazepam, but not pentobarbital, was associated with carry-over effects. The diazepam-produced deterioration in mood and social behavior was a subtle effect observed in a population for which usual therapeutic indications were lacking and at higher than usual therapeutic doses. The syndrome may, however, occur with long-term diazepam use or misuse in therapeutic settings and, hence, warrants clinical awareness in monitoring the course of treatment.

Adolescent↗
PubMed1993

Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam.

OBJECTIVE: The current study examines whether antidepressants, contrary to current thinking, are safe and effective treatments for generalized anxiety disorder (GAD) not complicated by depression or panic disorder. DESIGN: Randomized, double-blind, placebo-controlled, flexible-dose, 8-week treatment study comparing imipramine hydrochloride (mean maximum daily dose, 143 mg), trazodone hydrochloride (255 mg), and diazepam (26 mg). PATIENTS: Two hundred thirty patients with a DSM-III diagnosis of GAD in whom major depression and panic disorder has been excluded, and who had a Hamilton Anxiety Scale total score of at least 18. SETTING: Seventy-five percent of patients were treated in family practice settings in the community, with the remainder treated in psychiatric practices, either academic or private. RESULTS: Patients treated with diazepam showed the most improvement in anxiety ratings during the first 2 weeks of treatment, with somatic symptoms being most responsive. From week 3 through week 8 trazodone achieved comparable, and imipramine somewhat better, anxiolytic efficacy when compared with diazepam, with psychic symptoms of tension, apprehension, and worry being more responsive to the antidepressants. Among completers, moderate to marked improvement was reported by 73% of patients treated with imipramine, 69% of patients treated with trazodone, 66% of patients treated with diazepam, but only 47% of patients treated with placebo. Overall, patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients, but attention rates were the same across all treatments. CONCLUSIONS: The results of the study need replication, but suggest a potentially important role for antidepressants, particularly imipramine, in patients suffering from GAD.

Adult↗
PubMedDate not supplied

Pharmacokinetics of diazepam from a controlled release capsule in healthy elderly volunteers.

A single dose open labelled two-way randomized crossover study was used to assess the pharmacokinetics of diazepam from a controlled release capsule relative to standard release tablets in elderly volunteers. Eighteen volunteers received a single 15 mg controlled release capsule or a 5 mg tablet t.i.d. on one day. Diazepam plasma concentrations were determined at specific times over a 96-h interval by an electron capture-gas chromatographic method. Mean plateau plasma concentrations endured from 2 to 24 h avoiding the peak to trough fluctuations associated with conventional t.i.d. dosing. Similar areas under the plasma concentration-time curve (AUC) values indicated equal extent of absorption between formulations and regimens. Comparing parameters in this same elderly population to a young adult population, previously administered the controlled release capsule, shows lower maximum concentrations and a longer plateau duration in the elderly volunteers. Although there is a twofold increase in the mean diazepam half-life in the elderly when compared to young adults, the estimated apparent volume of distribution increased proportionately with half-life to maintain a constant clearance. Thus, the total body clearance of diazepam appears to be age independent. The age-dependent pharmacokinetics observed in this study are consistent with previously reported data involving diazepam. Overall, the controlled release capsule administered once daily mimics a t.i.d. regimen in elderly volunteers.

Adult↗
PubMedDate not supplied

Bioinequivalence of a generic brand of diazepam.

Twenty-six healthy male volunteers received a single 10 mg dose of diazepam on two occasions in a crossover bioequivalence study comparing the reference product (Valium) and a generic formulation (NeoCalme). Concentrations of diazepam and its metabolite, desmethyldiazepam, were determined during 264h after each dose. Peak plasma diazepam concentrations were significantly lower for NeoCalme vs Valium (247 vs 394 ng ml-1, p less than 0.001) and reached significantly later after the dose (1.62 vs 0.98 h, p less than 0.001). Total area under the plasma concentration curve (AUC) was also significantly lower for NeoCalme (6614 vs 7552 ng ml-1 x h, p less than 0.001), although AUC ratios for NeoCalme divided by Valium satisfied the '75-75' guidelines. Findings for desmethyldiazepam were similar. Thus, diazepam absorption from the generic brand of diazepam is significantly slower than from Valium, which in turn could lead to therapeutic inequivalence.

Adult↗
PubMed1976

Effect of diazepam on ventilatory responses.

To investigate the effects of diazepam on ventilatroy control, hypoxic and hypercapnic ventilatory responses were studied in 8 normal subjects before and after 10 mg of intramuscular diazepam. There was no significant change in either resting minute ventilation or resting end-tidal CO2 tension, but depression of hypoxic ventilatory response was observed 15 (60% of control) and 30 min (53% of control) after diazepam (p less than 0.05). No significant depression of hypercapnic ventilatory response was noted 70 to 130 min after diazepam. In view of the depression of hypoxic ventilatory response by diazepam in normal subjects, adverse responses along these lines should be considered in patients with impaired ventilatory function, such as chronic airways obstruction, and in those encountering acute hypoxemia.

Adolescent↗
PubMed1979

Inter- and intrasubject variation in diazepam free fraction.

The extent of intersubject variation in diazepam free fraction was measured in fasting plasma of 74 unrelated subjects. Free fraction differences between subjects were significant and ranged from 0.97% to 1.99%. Diazepam free fraction in 29 males was normally distributed about a mean of 1.25% (range, 1.05% to 1.47%), but the distribution in females was skewed to higher free fractions and 40% had values above the highest in males. Albumin concentration (r = -0.27, p less than 0.002) and age (r = 0.44, p less than 0.001) only accounted for a small part of the variation. Within-pair variances were not greater in 11 dizygotic than in 18 monozygotic twin pairs, indicating a greater contribution of environmental than of genetic factors to diazepam binding. The prehemodialysis free fractions of diazepam in 9 uremic patients ranged from 3.44% to 6.69%, and decreased (p less than 0.005) in 7 after 6 hr of hemodialysis. In 10 subjects determination of intrasubject variation in diazepam free fraction between 14-hr fasting and 2-hr postprandial plasma samples indicated that because subjects differ in their pattern of change in free fraction (p less than 0.001), the overall decrease in mean free fraction did not achieve statistical significance (p = 0.10). The mean relative percent change in free fraction within subjects after feeding was 15.2%.

Adult↗
PubMedDate not supplied

Comparative protein binding of diazepam and desmethyldiazepam.

The extent of plasma protein binding of diazepam (DZ) and its major metabolite, desmethyldiazepam (DMDZ), was determined by equilibrium dialysis in plasma samples drawn from 62 nonfasting unheparinized volunteers aged 20 to 85 years. The free fraction for diazepam averaged 1.48 per cent (range 0.85 to 2.30 per cent) and increased with age (r = 0.33). Desmethyldiazepam also was extensively bound. The mean free fraction was 2.97 per cent (range 1.78 to 5.28 per cent) and increased with age (r = 0.27). Free fractions for both diazepam and desmethyldiazepam were negatively correlated with plasma albumin concentration (r = --0.17 and --0.39). However, age, sex, and albumin explained only a small proportion of variability in free fraction for either compound. Free fraction for desmethyldiazepam always exceeded that for diazepam, and the two were correlated (r = 0.32). Thus, at any given total plasma concentration, the unbound concentration of desmethyldiazepam will exceed that of diazepam.

Adult↗
PubMedDate not supplied

Comparison of buspirone and diazepam in generalized anxiety disorder.

A total of 66 outpatients meeting Diagnostic and Statistical Manual (DSM-III) criteria for generalized anxiety disorder began treatment in a randomized double-blind study that compared the efficacy and safety of buspirone and diazepam. Thirty-nine outpatients completed the 4-week trial. Both drugs were administered in a 1:1 dosage ratio; the daily prescribed dose did not exceed 40 mg. The mean daily dose of buspirone prescribed throughout the study was significantly higher than that of diazepam. Diazepam had a significantly earlier onset of efficacy than buspirone, although both drugs were equivalent after 4 weeks of treatment. Adverse reactions were more frequent in the diazepam group. Total scores from the Hamilton anxiety scale and physician's global ratings show that diazepam was significantly superior to buspirone during the initial 2 weeks of treatment. These findings are further corroborated by the results of patients' self-rated scales.

Adolescent↗
PubMed2003

Prediction of the adsorption of diazepam by activated carbon in aqueous media.

Adsorption isotherms for the diazepam-activated carbon system in simulated intestinal fluid (SIF), without pancreatin, and in SIF with different percentages of ethanol were determined as were the solubilities of diazepam in SIF and in SIF with different percentages of ethanol. The surface area of the activated carbon was also evaluated. The results from the experimental work provided information on the relationship between adsorption and solubility. An excellent logarithmic relationship was observed between the adsorption affinity and the solubility of diazepam in the ethanol-SIF mixtures. This relationship was explained by a linear relationship between the differential free energy of displacement and the differential free energy of solution. Excellent correlations were also observed between the amounts of diazepam adsorbed by activated carbon and the solubilities of diazepam in the ethanol-SIF mixtures. This relationship was used to predict the complete isotherm, which was in excellent agreement with the experimental work.

Adsorption↗
PubMed1986

Effects of combined administration of diazepam and imipramine hydrochloride in rats.

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50 mg/kg) and/or diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5 mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100 g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydrochloride plus diazepam treatment group did not show increased imipramine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pharmacokinetics of diazepam in the rat: influence of a carbon tetrachloride-induced hepatic injury.

The pharmacokinetics of diazepam in normal rats and in rats pretreated with carbon tetrachloride to induce hepatic cirrhosis (cirrhotic rats) was studied after intravenous and oral administration of the drug (4 mg/kg). Animals pretreated with this hepatotoxic agent showed a significant prolongation in the half-life of diazepam in plasma that is due more to an increase in volume of distribution rather than to a decrease in clearance. This study confirmed that diazepam was highly extracted by the rat liver and was not affected by the hepatotoxic agent, although there probably was a saturation of the activity of the cytochrome P450 enzyme when the drug was administered orally. Diazepam binds to plasma proteins to a high degree in both normal and cirrhotic rats; however, in the latter, a significant increase in the fraction of unbound drug in plasma was observed. Pretreatment of rats with carbon tetrachloride did not produce any change either in the distribution of diazepam into erythrocytes or in the disposition of the metabolite desmethyldiazepam.

Administration, Oral↗
PubMed1979

Prevention by diazepam of adverse effects of maternal restraint stress on postnatal development and learning in the rat.

Rats on days 12--14 of pregnancy were treated with restraint stress alone (9h daily), restraint stress plus diazepam (1 mg/kg, twice daily), diazepam alone, or left as untreated controls. Postnatal development and behaviour was assessed on a wide-ranging battery of tests. Offspring of mothers subjected to restraint stress alone were significantly retarded on a number of developmental measures including growth, ear-opening, cliff avoidance response, auditory startle response and mid-air righting reflex. When adult these offspring also showed significantly impaired learning ability in a swimming maze. However, the rate of development and learning ability in the restraint plus diazepam or diazepam alone groups was comparable to or slightly advanced of that in untreated controls. It is concluded that concurrent administration of a low dose of the tranquiliser diazepam during restraint stress prevents the adverse postnatal effects of maternal restraint stress.

Animals↗