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PubMed1988

Effects of a perfluorochemical blood substitute on diazepam binding by human albumin.

The binding of 0.4 microgram mL-1 diazepam and 0.75 mol diazepam mol-1 of albumin by a perfluorochemical (PFC) emulsion, Fluosol-DA, 20%, by human serum albumin (HSA), and by their mixtures, has been examined at ambient temperature. The concentration of free diazepam was determined by standard centrifugation followed by supernatant ultrafiltration. Non-specific loss of diazepam occurred to the ultrafiltration device. This loss was independent of drug concentration and a correction factor was employed to calculate the true free diazepam concentration. Diazepam was extensively bound by the PFC emulsion. The percent free diazepam increased as the emulsion concentration decreased, while the binding of diazepam appeared to be independent of drug concentration. Diazepam did not partition into the pure PFC liquids, indicating that emulsion-bound diazepam is only associated with the emulsifiers of the droplets. Diazepam was extensively bound by HSA and the percent free diazepam increased as drug concentration increased or as HSA concentration decreased. The PFC emulsion significantly displaced HSA bound diazepam in all mixtures examined. Studies with the individual and combined components of the emulsion indicated that this displacement is largely attributed to the oleic acid component and, to a much smaller degree, the Pluronic F-68 component of the emulsion.

Blood Substitutes↗
PubMed1996

Influence of the carrier on the intrinsic rate of dissolution of diazepam in interactive mixtures.

The use of interactive mixtures of drugs adhering to the surface of carriers can promote drug dissolution. The mechanism of dissolution of such mixtures has been studied using the rotating-disc method under conditions eliminating secondary influences such as carrier surface characteristics and drug particle aggregation. Levich plots were used to characterize the dissolution behaviour. Diazepam-compactrol interactive mixtures had initial dissolution rates similar to that of pure diazepam owing to the deposition of a continuous layer of diazepam on the disc surface from the interactive mixture. Linear Levich plots were produced at all drug loadings and the presence of compactrol in the disc slightly enhanced dissolution rates. Dissolution rates for diazepam-emcompress interactive mixtures were lower than those of pure diazepam. The Levich plots for these systems were non-linear with increasing negative curvature as the diazepam loading decreased. The rate of dissolution of diazepam in the lactose interactive mixture was markedly higher than that of pure diazepam, but high diazepam loadings in the lactose mixtures inhibited diazepam dissolution. Rapid carrier dissolution caused surface retraction of the disc, enhancing the dissolution rate. The Levich plots showed an upward curvature due to turbulence. Linear Levich plots for diazepam and other benzodiazepines and for diazepam-compactrol interactive mixtures showed that their dissolution in pH 5 phosphate buffer was diffusion-controlled. The Levich plots for diazepam-emcompress interactive mixtures were indicative of some interfacial control during dissolution, but the hypothesis of common ion precipitation of dissolved carrier, calcium phosphate, onto the disc surface did not fully explain this effect.

Diazepam↗
PubMed1989

[Studies on development of radioimmunoassay for diazepam and it's medicolegal application].

A sensitive radioimmunoassay was developed for the determination of diazepam. Detection of diazepam in tissues of rats and in blood from unnatural death victims and traffic accident victims was examined by this procedure. Antisera capable of binding [3H] diazepam were obtained by repeated immunization of rabbits with temazepam (oxydiazepam)-3-hemisuccinate conjugated to bovine serum albumin. The antibody of a 1: 10000 dilution could bind approximately 50% of the added radioactivity. The level at least as low as 1 pg of diazepam could be detected by this procedure. This antibody strictly recognized the existence of the methyl group at the position-1 and of the keto group at the position-2 of the benzodiazepine ring, and was highly specific for temazepam and diazepam among benzodiazepine derivatives. But other benzodiazepine derivatives had no cross-reactivity with this antibody. The distribution of diazepam in biological fluids and tissues of rats 1, 2, 4 and 8 hr after intraperitoneal injection was examined. The level of diazepam in serum, saliva, brain and bone marrow declined within 2 hr, while the level in liver and kidney was maximum 2 hr after administration. The concentration of diazepam in each tissue leveled off 4 hr after administration. Among these results the remarkable finding was that the concentration in the bone marrow is much higher than that in serum, saliva and brain, appearing to be due to a high accumulation of diazepam in this tissue. This result indicates that the bone marrow is a very useful material for the detection of diazepam in skeletonized remains. There ware good correlations (gamma = 0.8595-0.9973) in the concentrations of diazepam between serum, saliva and brain, and bone marrow. Detection of diazepam in blood from unnatural death victims and traffic accident victims were examined. Diazepam was identified in 3 cases of 50 unnatural death victims and in 4 cases of 48 traffic accident victims.

Animals↗
PubMed1983

Discriminative stimulus effects of diazepam in rats: evidence for a maximal effect.

Rats were trained to discriminate between saline and either 0.3, 1.0, 3.0 or 6.0 mg/kg of diazepam in a two-choice, discrete-trial avoidance procedure. Diazepam, chlordiazepoxide, flurazepam and pentobarbital occasioned dose-related increases in diazepam-appropriate responding in all four training dose groups. Increasing the training dose of diazepam from 0.3 to 1.0 mg/kg resulted in approximately a 3-fold shift to the right in the dose-effect curves for each of these four drugs. However, increasing the training dose to 3.0 or 6.0 mg/kg did not result in additional, concomitant shifts in these dose-effect curves. Moreover, the dose-effect curves of nine additional benzodiazepine analogs also did not differ markedly in rats trained with either 1.0 or 3.0 mg/kg of diazepam. The nonbenzodiazepines ethanol, phencyclidine, cyproheptadine and ketocyclazocine failed to produce diazepam-like discriminative stimuli in rats trained with either 0.3, 1.0 or 3.0 mg/kg of diazepam. In rats trained with 1.0 mg/kg of diazepam, Ro 11-6896, but not its inactive stereoisomer Ro 11-6893, occasioned diazepam-appropriate responding. Furthermore, the selective benzodiazepine antagonist CGS8216 blocked the effects of diazepam but not the diazepam-like effects of pentobarbital. These results demonstrate that the discriminative effects of diazepam are qualitatively similar across this 20-fold range of training doses; quantitatively, the discriminative effects of diazepam appear to reach a maximum and plateau above a training dose of 1.0 mg/kg in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Factors affecting diazepam infusion: solubility, administration-set composition, and flow rate.

The sorption of diazepam in large-volume i.v. admixtures to administration-set components and in i.v. containers was analyzed quantitatively. Solubility of diazepam in phosphate buffer at various pH levels and in i.v. fluids was measured. Partition coefficients of diazepam into components of i.v. administration sets and i.v. containers were studied by shaking a solution of diazepam in 0.9% sodium chloride, with finely cut components and measuring the change in diazepam in the aqueous phase. Flow studies through an administration set of a 0.04-mg/ml diazepam solution in 5% dextrose injection were done, varying both the flow rate and the length of tubing. The maximum free-base solubility of diazepam in phosphate buffer was 0.048 mg/ml; its solubility was 0.058, 0.050, and 0.064 mg/ml in lactated Ringer's, 0.9% sodium chloride, and 5% dextrose injections, respectively. Equilibrium partition coefficients were highest for polyvinyl chloride tubing and flexible bags. Volume-control sets made of cellulose propionate had lower but sufficiently large partition coefficients to cause diazepam loss. Polyolefin semi-rigid and glass containers had low partition coefficients. In the flow studies, the amount of solution-contact time correlated with the extent of absorption. As flow rate decreased or tubing length increased, the amount of diazepam absorbed increased proportionately. A nomogram and a predictive dosing chart are presented for calculation of actual diazepam doses delivered at various flow rates and tubing lengths. Diazepam can be administered safely and effectively by i.v. infusion. The use of volume-control sets and flexible polyvinyl chloride bags should be avoided with diazepam solutions. Polyolefin semi-rigid containers are acceptable alternatives to glass. The concentration of diazepam infusions should not exceed 0.04 mg/ml.

Absorption↗
PubMed1991

Effects of diazepam on nociception in rats.

Acute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg-1 day-1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency. Diazepam injected intracerebroventricularly (1, 5, 20 micrograms/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 micrograms/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency. These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

Animals↗
PubMed1982

Diazepam plasma binding in the perinatal period: influence of nonesterified fatty acids.

The plasma binding of diazepam was determined serially in 24 women undergoing either elective induction of labour (vaginal or emergency caesarean delivery) or elective caesarean section at term and in 5 nonpregnant women requiring abdominal surgery. In the majority of pregnant patients, a marked increase in diazepam percentage free was observed during labour or prior to caesarean section, reaching a maximum, 1.6 to 3.2 fold increase at delivery or within 4 h postpartum; by the fifth day postpartum, diazepam percentage free was lower than on admission to hospital. In contrast, little change in diazepam percentage free was observed during the perisurgical period in nonpregnant patients. In parturient and surgical patients, the time courses of diazepam percentage free and plasma nonesterified fatty acid (NEFA) concentration were parallel. Bivariate regression analyses of pooled data demonstrated a strong correlation (r = 0.642, p = less than 0.010 between diazepam percentage free and corresponding NEFA concentration and a weaker correlation between diazepam percentage free and both albumin (r = 0.319, p less than 0.02) or total protein (r = 0.438, p less than 0.01). From multiple linear regression it was demonstrated that 54% of the variability in diazepam percentage free could be attributed to plasma NEFA and albumin concentrations. NEFA displacement of plasma bound diazepam was substantiated using crystalline human serum albumin. An approximate 65% increase in plasma alpha 1 acid glycoprotein levels was observed posttrauma in both parturient and surgical patients but was unrelated to diazepam binding events. A relationship between diazepam plasma binding changes and concurrently altered disposition of diazepam during parturition is postulated.

Adult↗
PubMedDate not supplied

Effect of orally administered misoprostol and cimetidine on the steady state pharmacokinetics of diazepam and nordiazepam in human volunteers.

The effects of misoprostol and cimetidine on diazepam pharmacokinetics were evaluated in order to determine whether the kinetic variables for diazepam and nordiazepam alone differ with the repeated oral administration of misoprostol and cimetidine to healthy adult volunteers. The trial was conducted as an open crossover study in 12 normal subjects, divided into two groups with all subjects receiving both regimens. Total study duration was 5 weeks. An initial clinical assessment, including blood biochemistry and assessment of subject oxidation status was carried out on study day 1. On this day, subjects began taking diazepam (10 mg) orally for one week, with pharmacokinetic studies performed at day 8, when steady state levels of diazepam were reached. This was followed by one week with active drug, misoprostol to Group I and cimetidine to Group II, with pharmacokinetic studies performed at the end of a 1-week treatment. After a 2-week wash-out period, both groups took for one week, the alternate drug, i.e. cimetidine plus diazepam to Group I and misoprostol plus diazepam to Group II. On days 8, 15 and 36, subjects were admitted to the hospital for 12 h, during which time a clinical examination was carried out and blood samples were taken at time zero and at 4, 8, 12, 24, and 36 h post-dosing for the measurement of serum diazepam and nordiazepam. The main parameters measured and evaluated were diazepam and nordiazepam pharmacokinetics at steady state (days 8, 15 and 36). These were areas under the curve in the dose intervals (AUC0-24h), maximum plasma concentrations (Cmax), time to peak concentrations (Tmax), elimination half-life (t1/2), elimination constant (Kel), distribution volume (Vd), total body clearance (ClB) and clearance after oral administration (Cloral). The results demonstrated that plasma diazepam and nordiazepam concentrations had a significant increase after steady states have been reached with the simultaneous administration of 800 mg of cimetidine daily for one week. The simultaneous administration of 800 micrograms of misoprostol did not cause any significant change in diazepam and nordiazepam plasma levels after steady states had been reached. Comparing the pharmacokinetic parameters of Groups A and B as well as within groups on days 8, 15 and 36, a significant increase in plasma diazepam and nordiazepam levels was detected. This was due to a cimetidine-induced impairment in microsomal oxidation of diazepam and nordiazepam, which caused a decrease in total metabolic clearance and increased mean steady state plasma concentrations. A more prolonged half-life was observed for both groups taking cimetidine as well as an increase of mean maximum plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed2003

Reduction of inflammation in rats by diazepam: tolerance development.

High doses of diazepam (10-20 mg/kg) were shown to reduce the volume of acute carrageenan-induced inflammatory paw edema in rats. This effect was not observed after adrenalectomy or long-term use of similar doses of diazepam. The present experiment was undertaken to analyze the effects of long-term (21 daily injections) treatment with diazepam (10 mg/kg) on both carrageenan-induced paw edema (CIPE) and corticosterone serum levels. For comparison, the effects of a single and acute 10 mg/kg dose of diazepam were also analyzed. Results showed that: 1- long-term diazepam treatment induced no changes in CIPE values and corticosterone serum levels; 2- acute diazepam treatment reduced CIPE values and increased corticosterone serum levels; 3- the plasmatic levels of diazepam measured 1 hour after the single treatment or 1 hour after the last dose of long-term diazepam administration were not different. These results indicate the development of tolerance to diazepam effects on both CIPE and corticosterone serum levels and suggest a relevant role for corticosterone on diazepam-induced inhibition of acute inflammation. Data were discussed in the light of peripheral benzodiazepine receptor site (PBR) activation within adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE. Possible actions of diazepam on HPA axis activity and/or on cytokine network were also discussed.

Animals↗
PubMed1992

Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time.

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12-hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased 1/4 to 2 1/2 hours after 5 mg diazepam, (maximum, +7.3%) and 3/4 to 12 hours after 10 mg diazepam (maximum, +15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Administration, Oral↗
PubMed2003

Physical dependence in baboons chronically treated with low and high doses of diazepam.

Physical dependence on diazepam was evaluated in male baboons chronically treated with either low or high doses of diazepam. Baboons received either a single oral daily administration of a low dose (0.5 mg/kg per day) of diazepam (n=4) or continuous intragastric infusion of a high dose (20 mg/kg per day) of diazepam (n=7). Development of physical dependence during chronic dosing with 0.5 mg/kg per day diazepam was assessed at 2 and 4 weeks and then monthly, during 1-h behavioral observations, following injections of the benzodiazepine competitive antagonist flumazenil. After 3-24 months of diazepam treatment, dosing was discontinued and physical dependence assessed via observation and responding for food pellets. In baboons that received 0.5 mg/kg per day diazepam, flumazenil precipitated a mild- to intermediate-intensity benzodiazepine withdrawal syndrome, which included decreases in the number of food pellets earned per day and increases in withdrawal postures, self-directed behaviors, aggressive behaviors and retching/vomiting. Three of four baboons showed signs of precipitated withdrawal after only 2 weeks of chronic low-dose treatment. Flumazenil continued to precipitate withdrawal signs, but with no systematic increase in severity, throughout the 6-10 months of 0.5 mg/kg diazepam administration. When 0.5 mg/kg per day diazepam dosing was discontinued, the number of food pellets earned per day decreased in two of the four baboons, but no systematic changes in behavioral signs were observed. In contrast, within 7-10 days of termination of 20 mg/kg per day diazepam dosing, withdrawal signs of intermediate intensity and a decrease in the number of food pellets earned per day occurred in all baboons. In the present study, physical dependence developed after 2 weeks of a chronic low dose of diazepam administration but did not increase further over long-term exposure to diazepam.

Animals↗
PubMedDate not supplied

Thrombophlebitis after intravenous diazepam--can it be prevented?

Although pain and subsequent thrombophlebitis are complications in patients receiving intravenous (IV) diazepam, the mechanism and accompanying histology are unknown. To further elucidate the pathogenesis for this and determine whether it can be minimized, adult female rats received IV diazepam, diazepam vehicle, lidocaine, a combination of lidocaine and diazepam, or N saline solution, and underwent subsequent tissue light microscopy. Vascular tissue from animals receiving IV diazepam alone revealed marked inflammation with inflammatory edema and intramural polymorphonuclear-cell infiltration. Intravascular thrombosis and complete vein-wall destruction were also present in some animals as early as 48 hours after IV diazepam. Diazepam vehicle and diluted diazepam produced similar morphologic alterations. Lidocaine or saline IV resulted in no histologic alterations, while lidocaine added to diazepam did not reduce the inflammatory response. These results represent the first systematic morphologic evaluation of vein response to intravascular diazepam and suggest that it produces rapid and detrimental morphologic alterations. The dilution of diazepam or combination with lidocaine does not appear to alter these findings, and diazepam vehicle appears to assume a role in the production of the vascular injury.

Animals↗
PubMed2003

Coexistence and concentrations of ethanol and diazepam in postmortem blood specimens: risk for enhanced toxicity?

Both ethanol and diazepam are classified as depressants of the central nervous system and exert their effects via the GABAA receptor complex. We report the coexistence and concentrations of ethanol, diazepam, and its primary metabolite nordiazepam in a case series of 234 forensic autopsies collected over a ten-year period. Diazepam, nordiazepam, and ethanol were determined in femoral venous blood by highly selective gas chromatographic methods. The mean (median) femoral blood concentrations were ethanol 0.24 g/100 mL (0.25 g/100 mL), diazepam (D) 0.23 microg/g (0.10 microg/g), nordiazepam (ND) 0.24 micro/g (0.20 microg/g), sum (D + ND) 0.43 microg/g (0.30 microg/g), and the ratio D/ND was 1.19 (1.0). When cause of death was attributed to alcohol and/or drug intoxication (N = 50), the mean and median blood-ethanol concentration was higher, being 0.36 g/100 mL and 0.38 g/100 mL, respectively, whereas the mean (median) and range of blood-diazepam concentrations were about the same, 0.23 microg/g (0.10 microg/g) and 0.05 to 1.2 microg/g. The femoral-blood concentrations of diazepam and nordiazepam were highly correlated (r = 0.73), but there was no correlation between the concentrations of ethanol and diazepam (r = -0.15). In another 114 fatalities (all causes of death) with diazepam and/or nordiazepam as the only drugs present, the mean (median) and range of blood-diazepam concentrations were 0.22 microg/g (0.10 microg/g) and 0.03 to 3.5 microg/g. The pathologists report showed that none of these deaths were classed as drug intoxications. The impression gleaned from this study of ethanol-diazepam deaths is that high blood-ethanol concentration is the major causative factor. We found no evidence that concurrent use of diazepam enhanced the acute toxicity of ethanol, although interpretation is complicated by the high blood-ethanol concentration (median 0.38 g/100 mL), making it difficult to discern an added effect of diazepam.

Central Nervous System Depressants↗
PubMed1992

Effect of electroacupuncture on the long-term diazepam-induced changes in regional GABA of mammalian central nervous system.

Single electroacupuncture (EA) exposure (10 Hz, 1 volt, 15 min) to long-term (15 consecutive days) diazepam (5 mg/kg/day, i.p.) treated adult male albino rats (120-140 g) potentiated the long-term diazepam-induced increase of GABAergic activity in thalamus (Th) but the long-term diazepam-induced inhibition of GABAergic activity in cerebral cortex (CC) and spinal cord (SC) was disinhibited under similar condition of treatment. These changes in brain regional GABAergic activity may be correlated with the inhibition of single EA-induced analgesia (EAA) under similar conditions of long-term diazepam treatment with single EA exposure. Single EA exposure alone, however, inhibited GABAergic activity in Th and pons-medulla (PM) with the development of EAA. Multiple EA (10 Hz, 1 volt, 10 min/day) exposure along with long-term diazepam for 15 consecutive days inhibited GABAergic activity in CC and SC which is similar to the effect observed with either multiple EA exposure or long-term diazepam alone. But in Th the multiple EA or long-term diazepam-induced increase in GABAergic activity was significantly potentiated with the co-treatment of multiple EA and long-term diazepam for 15 consecutive days. Although GABAergic activity in PM under multiple EA or long-term diazepam treatment alone was not affected their (EA and diazepam) co-exposures under long-term conditions significantly enhanced GABAergic activity in PM. These region specific characteristic changes in central GABAergic activity under long-term treatment of diazepam along with EA may thus explain the potentiation of multiple EA or long-term diazepam-induced analgesia (tail flick latency).

Animals↗
PubMed1981

Solubility characteristics of diazepam in aqueous admixture solutions: theory and practice.

The solubility of diazepam was investigated to determine compatibility limits for diluting diazepam injection in four large-volume parenteral (LVP) solutions. A solution of diazepam powder (15 mg/ml) in absolute alcohol and of the commercially available diazepam injection (5 mg/ml) were used in the study. Either 1.0 ml of the alcoholic solution or 3.0 ml of the commercial injection were added to 50 ml of the LVPs studied-sterile water for injection (WFI), 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection. Diazepam was assayed sprectrophotometrically at 367 nm. The solubility of diazepam in WFI was 0.041 mg/ml after equilibration for 24 hours at 25 degrees C. The solubility of diazepam in the LVPs ranged from 0.04 to 0.05 mg/ml at 25 degrees C. The effects of solution dielectric constants on nonelectrolyte solubility and the minimal fraction of protonated (ionized) diazepam present in typical admixtures are deduced to be negligible determinants of diazepam solubility in i.v. solutions at pH greater than or equal to 5.4 prepared from greater than or equal to 1:10 volume dilutions of diazepam injection. The aqueous solubility data for diazepam corroborate other reported values and are tantamount to recommending against less than a 1:100 volume dilution of diazepam injection when compounding i.v. admixtures.

Diazepam↗
PubMedDate not supplied

The relaxant effect of diazepam on rat tracheal strips.

The effect of diazepam was studied on the rat isolated trachea precontracted with acetylcholine 10-3M. Diazepam induced a dose dependent relaxant effect EC50 values 2.02 +/- 0.28.10(-4)M in controls (n = 38). The effect of diazepam was not modified by flumazenil (10-(6) to 10-(4) M) or RP 52028 (10-(6) to 10-(4)M) which are antagonists of central and peripheral benzodiazepines receptors respectively. No antagonism was observed between diazepam and nucleotides or endogenous ligands (adenosine 10(-6) to 10(-4)M, UTP 10(-6) to 10(-4)M, hématoporphyrin 10(-5) and 10(-4)M or nicotinamide 10(-5) and 10(-4)M). These results excluded an endogenous ligand-mediated interaction between nucleotides and diazepam. Propranolol (10(-7)M) did not modify the diazepam-induced relaxation, which excluded an involvement of beta receptors in diazepam relaxation. Theophylline (10(-7) and 10(-6)M), IBMX (10(-5) and 10(-4)M) rolipram (10(-5) and 10(-4)M) and siguazodan (10(-6) to 10(-4)M) displayed to the left the concentration-response curves to diazepam. The adenylcyclase activator forskolin (10(-7) to 10(-5)M, the beta adrenor stimulant isoprenaline (3.10(-5)M) and the direct acting G stimulant NaF (10(-3)M) also produced a leftward shift in the diazepam concentration-response curve. The relaxant concentration-effect curves to isoprenaline and to sodium nitroprusside were shifted to the left in a concentration-related manner by diazepam. Diazepam was more potent on the isoprenaline than on nitroprusside-induced relaxation. These results suggest that the diazepam-induced relaxation in the rat isolated trachea is mediated by an inhibition of cyclic nucleotide phosphodiesterases.

Animals↗
PubMed1984

Relative abuse liability of diazepam and oxazepam: behavioral and subjective dose effects.

The effects of diazepam (10-160 mg) and oxazepam (30-480 mg) were studied in volunteers with histories of drug abuse. Oral doses were administered every third day under double-blind and counterbalanced conditions. Dose-effects with area under the time-action curve data (AUC) showed diazepam to be 2.6-5.7-times more potent than oxazepam on various psychomotor, cognitive, staff-rated, and subjective measures. Comparison of relative potencies showed diazepam to be relatively more potent in producing 'liking' than in producing psychomotor and cognitive effects. Diazepam produced greater peak effects than oxazepam on a number of staff- and subject-rated measures, including liking. Onset of effect was more rapid and time to maximal effect was shorter (1-2 h versus 4-12 h) with diazepam than oxazepam, while time to offset of effect was similar for the two drugs. Diazepam was categorized as producing barbiturate-like subjective effects (38.3%) more frequently than was oxazepam (13.8%), while oxazepam was identified as placebo more often than diazepam. Repeated administration of 160 mg diazepam and 480 mg oxazepam showed that AUC liking was greater for diazepam than oxazepam and that tolerance to psychomotor and cognitive effects occurred with oxazepam but not diazepam. This study suggests that diazepam may have a higher abuse liability than oxazepam.

Adult↗
PubMed1981

The effect of chronic diazepam treatment on discrimination performance and 3H-flunitrazepam binding in the brains of shocked and nonshocked rats.

The purpose of the present study was: (1) to investigate the effects of unavoidable shock on an appetitively motivated discrimination task; (2) to evaluate the effect of chronic diazepam treatment on the performance of a previously learned discrimination task in shocked and nonshocked animals; (3) to measure the binding of 3H-flunitrazepam (an analogue of diazepam) to selected brain regions of chronically diazepam-treated shocked and nonshocked rats, in comparison to saline-treated controls. Results indicated that unavoidable shock significantly interfered with the learning of a new, nonshock-related discrimination task. The effect of chronic diazepam treatment on the performance depended on the previous experience of the animal; chronic diazepam treatment significantly improved the maze performance of shocked animals. On the other hand, chronic diazepam treatment in the nonshocked animals tended to interfere with the performance of the discrimination task. Neurochemical data showed significant reduction in 3H-flunitrazepam binding to diazepam receptors in membranes from the brains of a nonshocked diazepam-treated (CD) group in comparison to a nonshocked saline-treated (CS) group. In contrast, the unavoidable shock-treated diazepam group (SD) showed opposite effects, the binding of 3H-flunitrazepam increasing significantly. A significant increase in the maximal binding sites in the frontal cortex from shocked rats treated with diazepam, compared to the nonshocked diazepam-treated rats, was detected by Scatchard analysis.

Animals↗