Plasma Concentrations Of Diazepam Research Articles

Estudio farmacocinético comparativo entre diazepam y midazolam, post administración intravenosa e intramuscular en avestruz doméstico (Struthio camelus)

El interés en el manejo de especies animales con fines experimentales y de estudios farmacocinéticos, por la necesidad de pautas terapéuticas más racionales, nos llevó a desarrollar el presente estudio. Se utilizaron seis avestruces juveniles sanos, a los que se administró diazepam (DZP) y midazolam (MDZ) vía IV e IM, a dosis única de O,5mg/kpv. En cuanto a DZP, la cuantificación por HPLC/UV(220nm) de los parámetros farmacocinéticos post administración IV, nos dieron los siguientes valores: MRTi=71,17±29,97min, t1/2β=49,30±21,18min, Cli=87±50mUkglmin y Vc=1,82±O,35L/kpv; mientras que las concentraciones plasmáticas post administración IM, no permitieron el tratamiento cinético. Para MDZ los parámetros farmacocinéticos post administración IV e IM corresponden respectivamente a MRTi=59,70±37,14 y 50,09±12,71min, 1/2β=39,64±25,30 y 35,32±1O,93min, Cli=37±20mL/kg/min y Vc=O,72±O,24L/kpv. La biodisponibilidad post administración IM fue 99,97±30,43% con Cmax=O,36±O,09 μ,g/mL y tmax=1l±2,24min. No se detectaron concentraciones plasmáticas de l-hidroxi-midazolam (metabolito activo). Existe una correlación entre los datos de laboratorio obtenidos y las observaciones clínicas in situ. Se concluye que DZP no fue una opción válida para tranquilización o inducción anestésica en avestruces juveniles. MDZ sí demostró una depresión del SNC significativa por ambas vías. La técnica analítica utilizada es confiable de acuerdo a los parámetros de validación empleados.

The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam.

The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.

Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes.

All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam (< 2 hours) and midazolam (3 to 4 hours) and longer for clonazepam (24 hours) and lorazepam (up to 72 hours), and is not correlated with the plasma concentration-time profiles of these drugs. Although a relationship between the plasma concentration of diazepam, lorazepam and midazolam and their pharmacodynamic effect has been demonstrated in healthy individuals, some caution is warranted as the clinical relevance of these data has not been clearly established. The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam. In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly. The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomized uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam. Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.

In-vitro effects of diazepam on human ciliary function

This study investigated the in-vitro effect of diazepam on human ciliary beat frequency (CBF) from 15 normal subjects using brush cytology. Tube A contained culture medium and tube B the diluent into which Diazepam was dissolved, and culture medium (controls). Tubes C, D and E contained, 0.4 mg/l, 4.0 mg/l and 40.0 mg/l of diazepam in culture medium, respectively. The mean effective diazepam concentration in plasma is 0.4 mg/l. CBF was measured photometrically. The most vigorous cilia were measured in five areas taking 10 readings on each sample, 30 min and 1 h after mixing. The SD and confidence limits were calculated along with significance testing (P < 0.05) using the paired t-test and ANOVA. The means of the CBF of tubes A and B were 13.44 ( SD 2.65) and 13.67 ( SD 2.48). There was a reduction of the CBF with increasing concentrations of diazepam at 30 min, 11.32 ( SD 2.14), 10.29 ( SD 1.58) and 4.14 ( SD 1.57) in tubes C, D and E, respectively. There was a significant lowering in CBF of 17% (P < 0.01) by diazepam at the mean effective plasma level (tube C) when compared against the controls. CBF decreased over time and at 1 h was 10.57 ( SD, 1.36), 9.02 ( SD, 1.39) and 3.58 ( SD, 1.31) in tubes C, D and E, respectively.

Pharmacokinetic and pharmacodynamic response after intranasal administration of diazepam to rabbits.

Nasal application of drugs might be an alternative to intravenous administration in acute situations such as epileptic or fever seizures. In the search for a nasal formulation leading to a peak plasma concentration of diazepam at a tmax < or = 5 min bioavailability in rabbits has been studied after intranasal administration of the drug in ten vehicles of different polarity. The animals were dosed with 3 mg diazepam, dissolved in 100 microL vehicle, the solution being administered into both nostrils. The bioavailability, measured during the first 30 min, because periods after this are not relevant for acute treatment, was found to be between 49 and 62% for the four most promising vehicles, pure glycofurol 75, tetraethyleneglycol, poly(ethylene glycol) 200 and 30% glycofurol in tetraethyleneglycol. The tmax for these vehicles was achieved after 5 min, and they induced a very rapid pharmacodynamic response after 1.5 to 3.5 min. The bioavailability was reduced when more polar liquids such as ethanol and tween 20, or lipid oils, e.g. vegetable oil and miglyol 840 were added to the glycofurol. There was a good correlation between tmax and the induction of pharmacodynamic response. These results suggest that nasal application of diazepam in a water-free low-molecular-weight glycol might be of clinical importance as an alternative to intravenous injection, especially in acute situations.

In vitro Effects of Diazepam on Human Ciliary Function

This study demonstrated the in vitro effect of diazepam on human ciliary beat frequency (CBF) from fifteen normal subjects using brush cytology. Tube A contained culture medium, tube B the diluent that diazepam intravenous injectate was carried in and culture medium (controls). Tube C, D and E contained, 0.4 mg/1, 4.0 mg/1 and 40.0 mg/1 of diazepam in culture medium respectively. The mean effective diazepam concentration in plasma is 0.4mg/l. CBF was measured photometrically. The most vigorous cilia were measured in 5 areas taking 10 readings on each sample, 30 minutes and 1 hour after mixing. Standard deviation (SD) and confidence limits were calculated along with significance testing (p < 0.05) using the paired t-test and ANOVA. The mean of the CBF of tubes A and B were 13.44 (SD 2.65) and 13.67 (SD 2.48). There was a reduction of the CBF with increasing concentrations of diazepam at 30 minutes, 11.32 (SD 2.14), 10.29 (SD 1.58) and 4.14 (SD 1.57) tubes C, D and E respectively. There was a significant lowering in CBF of 17% (p<0.01) of diazepam at the mean effective plasma level (tube C) when compared against the controls. CBF decreased over time and at 1 hour was 10.57 (SD, 1.36), 9.02 (SD, 1.39) and 3.58 (SD, 1.31) tubes C, D and E respectively. A proposed mechanism of altered intracellular calcium flux via the action diazepam on GABA receptors is described.

Absorption of diazepam after its rectal administration in dogs

SUMMARY A cross-over study was performed in 6 healthy mixed-breed dogs and 4 healthy Beagles. Diazepam was administered per rectum to Beagles (0.5 mg/kg of body weight) and mixed-breed dogs (2 mg/kg), and iv (0.5 mg/kg) to both groups of dogs. Each dog received the drug by both routes, with a 1-week washout period between dosages. After diazepam administration, blood samples were collected to measure plasma concentration of diazepam and its active metabolites, desmethyldiazepam and oxazepam, by use of reverse-phase high-performance liquid chromatography (hplc). Systemic availability was assessed by comparing the area under the curve for diazepam metabolites for each route of administration. Mean (± sd) diazepam concentrations in plasma after rectal administration were low in comparison with those obtained after iv administration, with systemic availability of only 7.4 (± 5.9) and 2.7 (± 3.2)% for the high and low dose, respectively. However, diazepam was converted to its metabolites within minutes after administration. Accounting for the total concentration of benzodiazepines (diazepam plus desmethyldiazepam and oxazepam) in plasma, systemic availability was 79.9 (± 20.7) and 66.0 (± 23.8)% for the high and low dosage, respectively. After iv administration, diazepam concentration decreased, with a half-life of only 14 to 16 minutes, but desmethyldiazepam and oxazepam concentrations decreased more slowly, with a half-life of 2.2 to 2.8 hours and 3.5 to 5.1 hours, respectively. Each of the metabolites is reported to have anticonvulsant activity. After rectal administration of the high dose, mean total benzodiazepine concentration was above 1.0 μg/ml within 10 minutes and was maintained above this concentration for at least 6 hours. We conclude that diazepam is absorbed after rectal administration in dogs, and that the pharmacologic effects are probably caused by the active metabolites, not the parent drug. Samples also were analyzed by use of a nonspecific commercial benzodiazepine fluorescence polarization immunoassay (fpia). Correlation between the fpia and hplc assay was strongest for diazepam (R2 = 0.84), weak for desmethyldiazepam (R2 = 0.09), and nonexistent for oxazepam. We conclude from a comparison of assays that hplc is preferred over the fpia method for measuring benzodiazepines in dogs.

Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4′-hydroxylation*

To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status. Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam. Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05). The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.

Relationship between unbound plasma concentrations and various psychomotor and subjective effects after intakes of diazepam and flunitrazepam

Unbound plasma concentrations of diazepam and flunitrazepam were related to psychomotor and subjective effects of the two drugs. The interindividual variability in plasma protein binding of both diazepam (98.5 +/- 0.14%) and flunitrazepam (84.5 +/- 1.2%) was relatively small, and high correlations were therefore observed between the individual unbound and total drug plasma concentrations after a particular dose. However, poor correlations were seen between individual unbound drug plasma concentrations and psychomotor or subjective effects. This observation indicates that factors other than individual variability in drug plasma concentration, account for the pronounced individual differences in, for example, psychomotor impairment frequently observed after intake of benzodiazepines. Furthermore, based on a linear relationship between unbound drug plasma concentrations and increase in either complex choice or simple reaction time, the potency of flunitrazepam was calculated to be about seven times higher than the potency of diazepam. This is approximately two times higher than expected from the reported in vitro affinity of the two drugs for the benzodiazepine receptor. This finding may indicate that flunitrazepam may have a higher apparent in vivo intrinsic efficacy than diazepam when assessed by psychomotor impairment.

Reaction time and diazepam plasma concentration in subjects with normal gastric pH

The present study investigated the relationship of reaction time with the plasma concentration of four different formulations of diazepam (liquid, original, new, and generic). On four separate days, over a 4-month period, subjects with normal gastric pH (N=7) were administered each of the diazepam formulations. Blood samples were obtained prior to each dose and at subsequent intervals. Likewise, reaction times were evaluated prior to dosing and then at ten different intervals post-dosing. As hypothesized, reaction time performance was associated with plasma diazepam concentration, regardless of formulation type. This suggests that reaction time is a sensitive measure of cerebral functioning for individuals who are treated with diazepam. In addition to providing a measure of drug effects on cognitive functioning, the results of this study have implications concerning possible hazards of operating machinery or driving motor vehicles for individuals being treated with diazepam.

Determination of diazepam and nordazepam in milk and plasma in the presence of oxazepam and temazepam

For studies on the excretion of drugs into milk a sensitive high-performance liquid chromatographic assay was developed to quantitate diazepam and nordazepam in the milk and plasma of humans and rabbits in the presence of their major metabolites, oxazepam and temazepam. Flurazepam was used as an internal standard. The assay involves extractions with diethyl ether and an additional acid clean-up step. Chromatographic separation was achieved by a LiChrospher 60 RP-select B (5 microns) column and KH2PO4- acetonitrile (69:31, v/v) adjusted to pH 2.80 as a mobile phase. The same extraction and chromatographic conditions were suited to both types of samples, milk and plasma. The limits of determination using ultraviolet detection at 241 nm was for diazepam 20 ng/ml and for nordazepam 15 ng/ml. The absolute recoveries of diazepam, nordazepam and flurazepam in human milk were 84, 86 and 92% and in human plasma 97, 89 and 94%, respectively. The within- and between-day accuracy and precision for diazepam and nordazepam in milk and plasma at all concentrations tested (20-1500 ng/ml) were better than 8%. The high fat content which occurs in rabbit milk presented no limitation for the extraction of lipophilic diazepam: the method was successfully used to monitor milk and plasma concentrations of diazepam and nordazepam in lactating New Zealand White rabbits during 26-h infusions of diazepam (1.4 mg/h).

Correlation of Delayed Peak Concentration with Infusion-Site Irritation following Diazepam Administration

Diazepam 10 mg/2 mL iv was administered undiluted over five minutes to nine healthy men on two separate occasions. The infusion site was evaluated before and after each infusion by subject assessment of pain on a severity scale of zero (none) to ten (most). Blood samples were collected at 0, 5, 20, 30, 45, and 60 minutes, and periodically for 72 hours postinfusion. Diazepam plasma concentrations were determined by HPLC. Concentrations at five minutes (end of infusion) ranged from 0 to 889 ng/mL. Maximum plasma concentration (Cmax) was observed at 5 minutes for 10 treatments, at 20 minutes for 7 treatments, and at 30 minutes for 1 treatment. The observed Cmax ranged from 221 to 889 ng/mL. When time to reach peak plasma concentration (tmax) was 5 minutes, the Cmax was significantly greater than when tmax was 20 minutes (670 +/- 87 vs. 267 +/- 40 ng/mL, p less than 0.005). The area under the curve did not differ significantly between these two groups. The pain score at the end of infusion ranged from zero to five and was inversely related to the concentration at five minutes (r2 = 0.45, p = 0.002). The association between venous irritation, a low plasma concentration at the end of the infusion, and a delayed Cmax suggests that diazepam precipitated in the vein.

Time-dependence in diazepam kinetics after repeated doses in man.

The time-dependence in diazepam kinetics after a single oral dose and after repeated oral doses was investigated in 5 healthy volunteers. Subjects took a single oral 5 mg dose of diazepam on two occasions, in the morning (09: 30) or in the evening (21: 30). Then they took repeated oral 5 mg doses once a day for 8 days every morning or every evening. After repeated oral doses as well as after a single oral dose, the mean peak total diazepam concentration in plasma (Cmax) tended to be higher in the morning trial. However, no difference was found in the mean elimination half-life.(t1/2), the area under the plasma concentration time-curve (AUC), the volume of distribution (Vd), or the total plasma clearance (CL) after repeated diazepam doses between morning and evening. The results found in the single dose study were essentially identical to the findings reported previously by our group.The time-dependence in diazepam kinetics was also found after repeated administrations. The mechanism of this time-dependency in the drug seems to be explained by the time-dependent variations in the rate of absorption from the gastro-intestinal tract and the rate of distribution of the drug. The plasma diazepam clearance significantly increased after repeated doses.

The Disposition and Placental Transfer of Diazepam in Cesarean Section

The disposition parameters and placental transfer of diazepam were determined from blood and both plasma total and free concentration data in five women who had not undergone labor and who received diazepam (5 mg intravenously for 2 minutes) 1 1/2 to 3 hours before cesarean section at term. All patients exhibited smooth log plasma free concentration-time profiles. In contrast, marked increases in plasma total (approximate 50% increase) and blood (approximate 40% increase) diazepam concentrations occurred at delivery. The plasma total and blood concentration fluctuations were associated with reciprocal variations in diazepam percent free in plasma. For each patient there was a substantial increase in plasma nonesterified fatty acid (NEFA) concentration during the surgical period. There was a significant correlation (p less than 0.02) between diazepam percent free and plasma NEFA concentration on the day of delivery, suggesting that the fluctuations in percent free, and hence plasma total and blood diazepam concentrations, were mediated in part by variations in plasma NEFA concentration. Disposition parameters were calculated for four of the patients; the mean free plasma clearance of diazepam was 42.5 ml/min/kg, similar to the mean value reported previously for nonpregnant women of comparable age. For each mother-infant pair at delivery the ratio of total plasma diazepam concentration in umbilical vein plasma to that in maternal vein plasma was considerably greater than unity (mean +/- SD = 1.73 +/- 0.47), whereas the corresponding ratio for free plasma diazepam concentration was near unity (0.92 +/- 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of Pharmacodynamics of Diazepam by Quantitative Pharmaco‐EEG

The relationship between the quantitative EEG variables and plasma levels after the administration of diazepam (DZ) or N-desmethyldiazepam (synthesized NDDZ) was evaluated by simultaneously measuring the power spectra for EEG with two biological markers and plasma concentrations. After a single DZ administration, the EEG change corresponding to sedation appeared rapidly and showed a short duration. A close relationship was found between these effects and changes in the DZ plasma concentrations. DZ and synthesized NDDZ had the same pharmacodynamic characteristics, but the main metabolic product of DZ (metabolite NDDZ) showed a different pharmacokinetic profile. A multiple administration of DZ or synthesized NDDZ caused some reduction in sedation at the steady-state. These results led to the conclusions that a single administration of DZ causes sedation of a short duration, and the main metabolic product of DZ (metabolite NDDZ) does not seem to contribute to sedation. In addition, the reduction in the pharmacological effect after continuous treatment with DZ depends not on autoinduction or interference, but on acute tolerance or adaptation.

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.

The disposition and placental transfer of diazepam in cesarean section.

The disposition parameters and placental transfer of diazepam were determined from blood and both plasma total and free concentration data in five women who had not undergone labor and who received diazepam (5 mg intravenously for 2 minutes) 1 1/2 to 3 hours before cesarean section at term. All patients exhibited smooth log plasma free concentration-time profiles. In contrast, marked increases in plasma total (approximate 50% increase) and blood (approximate 40% increase) diazepam concentrations occurred at delivery. The plasma total and blood concentration fluctuations were associated with reciprocal variations in diazepam percent free in plasma. For each patient there was a substantial increase in plasma nonesterified fatty acid (NEFA) concentration during the surgical period. There was a significant correlation (p less than 0.02) between diazepam percent free and plasma NEFA concentration on the day of delivery, suggesting that the fluctuations in percent free, and hence plasma total and blood diazepam concentrations, were mediated in part by variations in plasma NEFA concentration. Disposition parameters were calculated for four of the patients; the mean free plasma clearance of diazepam was 42.5 ml/min/kg, similar to the mean value reported previously for nonpregnant women of comparable age. For each mother-infant pair at delivery the ratio of total plasma diazepam concentration in umbilical vein plasma to that in maternal vein plasma was considerably greater than unity (mean +/- SD = 1.73 +/- 0.47), whereas the corresponding ratio for free plasma diazepam concentration was near unity (0.92 +/- 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Diazepam during Multiple Dosing of a 6-mg Controlled-Release Capsule Once Daily

Sixteen subjects completed a two-way crossover study designed to determine the steady-state pharmacokinetic profiles of diazepam and desmethyldiazepam following a 6-mg controlled-release (CR) capsule dosed once daily compared with those of a 2-mg diazepam tablet dosed 3 times a day. Treatment A consisted of 14 days of CR dosing followed by 10 days of tablet dosing. Treatment B was the reverse of Treatment A. Plasma concentrations of diazepam and desmethyldiazepam were determined by an electron-capture gas-liquid chromatographic method. The areas under the diazepam plasma concentration-time curve were similar for both formulations at initiation of dosing and at steady-state, indicating comparable extents of absorption. The mean ratios of the areas at steady-state were near unity--0.94 for Treatment A and 0.91 for Treatment B--implying that no changes in steady-state conditions occurred upon switching regimens in either direction. The steady-state profiles of desmethyldiazepam were also comparable for the two dosage forms. These data indicate that the CR capsule and the conventional tablet t.i.d. produce similar target concentrations of both the drug and metabolite; therefore, these two dosage forms and dosing regimens should be interchangeable.

Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines.

The effect of diazepam on brain 5-HT-mediated neuroendocrine responses was studied in healthy male volunteers. An acute dose of diazepam (15 mg) significantly attenuated the prolactin and growth hormone responses to intravenous L-tryptophan. After 3 weeks administration of diazepam (25 mg/d) these responses had returned to normal despite much higher plasma diazepam concentrations, suggesting that tolerance had occurred. A reduction in brain 5-HT function may underlie some of the acute therapeutic actions of benzodiazepines. It is possible that excessive 'rebound' 5-HT activity may contribute to the abstinence syndrome seen on benzodiazepine withdrawal.

Famotidine: a notable lack of drug interactions.

Cimetidine, an H2-receptor antagonist, has been shown to inhibit the oxidative metabolism of several drugs by interacting with the hepatic cytochrome P450 system, which is involved in phase-I oxidative drug metabolism. Ranitidine, another H2-receptor antagonist, has been shown to have an extremely low level of interaction with the cytochrome P450 system. The potential of famotidine, a new H2-receptor antagonist with a guanylthiazole ring structure, to interact with the cytochrome P450 system has been extensively evaluated. Many of the studies used cimetidine and/or ranitidine as active controls. In vitro studies investigated the potential effects of famotidine coadministration on aminopyrine and diazepam demethylase activity, disturbances of P450 spectra, and effects on the metabolism of specific substrates such as deethylation of 7-ethoxycoumarin and demethylation of benzphetamine. Famotidine and ranitidine showed negligible interaction with the cytochrome P450 reactions studied, in contrast to the rather marked interaction demonstrated with cimetidine. Several in vivo animal studies investigated the effect of famotidine on hexobarbital sleeping time; plasma concentrations of diazepam, warfarin, and propranolol; antipyrine elimination kinetics; and warfarin prothrombin complex activity. Famotidine and ranitidine demonstrated either no evidence or minimal evidence of interaction with cytochrome P450 functions, in direct contrast to marked interactions produced by cimetidine. Human studies investigated the potential of an interaction with the coadministration of famotidine and aminopyrine, antipyrine, diazepam, theophylline, phenytoin, and warfarin. Coadministration of famotidine had no effect on the pharmacokinetic variables of theophylline, diazepam, desmethyldiazepam, and phenytoin and no effect on the half-life of antipyrine and aminopyrine or on the prothrombin time ratios associated with warfarin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)