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Plasma diazepam and N-desmethyl diazepam concentrations were measured in patients receiving diazepam 5 mg or 10 mg i.v. at 4-h intervals for periods of 6-22 days. At both doses there was an accumulation of both diazepam and its metabolite, the latter reaching concentrations of up to two to three times that of the parent drug. Plasma diazepam concentrations reached a plateau after 8 days while the concentration of N-desmethyl metabolite continued to increase throughtout the period of drug administration. On discontinuation of diazepam therapy both diazepam and N-desmethyl diazepam concentrations decreased slowly, the former with a half-life of 2-4 days and the latter with a half-life of 4-8 days.

A highly sensitive and selective glass capillary gas chromatographic negative ion chemical ionization mass spectrometric assay was developed to measure peptidoaminobenzophenone(2-o-chlorobenzoyl-4-chloro-N-methyl-N'-glycylglycinanilide) and its metabolites; chlorodiazepam, chlorodesmethyldiazepam and lorazepam in human plasma. As peptidoaminobenzophenone underwent pyrolysis during gas chromatography, it was converted to a thermally stable aminoquinolone. Internal standards for these compounds were the respective deuterium labelled compounds. Calibration curves were prepared for the range of 1-100 ng ml-1. Interference by endogenous substances was negligible in the isobutane negative ion chemical ionization mode in contrast to the electron impact or positive ion chemical ionization mode. This method was used to determine the plasma levels in humans following oral administration of two 5 mg doses.

1 Visuo-motor coordination has been used to study the immediate and residual effects of benzodiazepines on performance in man. The technique provides dose and time response data related to the decrement and the persistence of impaired performance. 2 With the overnight ingestion of flurazepam hydrochloride 30 mg and nitrazepam 10 mg, performance was impaired to 16 h and, at least, 19 h, respectively. Performance was not impaired after the overnight ingestion of diazepam, 5 and 10 mg, temazepam 10, 20 and 30 mg or oxazepam 15 and 30 mg. However, with temazepam 30 mg there was a trend toward impaired performance,, and with oxazepam 45 mg, performance was impaired 10 h after ingestion. With morning ingestion, coordination was impaired 0.5 and 2.5 h after diazepam 10 mg, at 0.5 h after temazepam 20 mg, and after oxazepam 30 mg at 2.5 and 4.5 hours. 3 The studies suggest that diazepam 5-10 mg, temazepam 10-20 mg and oxazepam 15-30 mg may be of use in the management of sleep disturbance when impaired performance the next day is to be avoided.

The cat has been used extensively as an experimental model for studying the pharmacology of compounds that exhibit CNS activity including diazepam and nordiazepam. However, since little is known about the distribution and elimination of diazepam in this species, the pharmacokinetics of diazepam and nordiazepam were studied in the cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam and 5 and 10 mg/kg of nordiazepam. The disappearance of diazepam and nordiazepam from blood was fitted with classical equations. Theoretical and trapezoidal areas under the curve (AUCth and AUCtr) were calculated. The volumes of distribution (Vd beta) were calculated as model-independent parameters for diazepam and nordiazepam. Intrinsic hepatic clearance, extraction ratio, and tissue binding parameters were also calculated for diazepam. From the observed data, it is apparent that the blood concentrations and the resulting areas under the curves are proportional to the dose of diazepam administered and that the pharmacokinetics of diazepam were linear over the dose range studied. In addition, nordiazepam formed after diazepam administration appeared to be proportional to the dose of diazepam administered. The terminal elimination rate constant of nordiazepam remained constant over the dose range studied. It appears that both diazepam and nordiazepam are highly bound to tissue. The total body clearance of diazepam (4.72 +/- 2.45 mL/min/kg) is approximately six times that of nordiazepam (0.85 +/- 0.25 mL/min/kg). Approximately 50% of an administered dose of diazepam was biotransformed to nordiazepam in the cat.

The interindividual variability of diazepam metabolism was studied using human livers. The formation of N-desmethyldiazepam (NDZ) and 3-hydroxydiazepam (temazepam, TMZ), was monitored by gas chromatography. In 10 livers, Km values for NDZ and TMZ formation varied independently from each other, each by a factor of 4, from 100 to 400 microM. This variability is consistent with the presence of at least two different cytochrome P-450 species controlling formation of these metabolites. In the same livers, Vmax for NDZ and TMZ production varied 6-fold and 15-fold, respectively.

Intracerebral (i.c.) injection of serotonin (5-HT) into mice induced head twitches in a dose-dependent manner at 10 min after injection. The head twitches induced by 5-HT (i.c.) were potentiated by the pretreatment of isocarboxazid (3 mg/kg i.p.), and inhibited by cyproheptadine (0.3 mg/kg i.p.), a 5-HT antagonist. Benzodiazepines such as fludiazepam and diazepam potentiated the head twitches induced by 5-HT (i.c.) in a dose-dependent manner. Mescaline (50 mg/kg i.p.) also induced head twitches in mice at 15 and 30 min after injection. Benzodiazepines potentiated the head twitches induced by mescaline in a dose-dependent manner. Cyproheptadine blocked the potentiating effect of benzodiazepines on the head twitches induced by both 5-HT (i.c.) and mescaline. By repeated administration of fludiazepam or diazepam for 5 days, the potentiating effect of both drugs on the head twitches induced by mescaline was unchanged and their anticonvulsant effects were not modified. In contrast, the potency of both drugs on muscle relaxation was significantly decreased by repeated administration. Benzodiazepines failed to change the uptake of 5-HT into the synaptosomal fractions from the rat brain. These results suggest that the pharmacological action of benzodiazepines is derived at least in part from their activating effect on 5-HT receptors.

The results quoted here suggest strongly that peptides as prodrugs are a real possibility for future forms of therapy. Pharmacokinetics and bioavailability are certainly altered by such modifications, usually in a positive sense. The possibilities in utilizing active transport permeases to direct drugs to the desired receptor are an obvious reality, and will undoubtedly lead to new methods for treating bacterial, fungal or even viral infections, and for improved ways of presenting anti-tumour agents. The number of patents appearing in this field is indicative of the interest shown in the pharmaceutical industry.

Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P less than .01) and with percent ideal body weight (r = .91, P less than .001). Eleven of the same subjects also received 5- to 15-mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P less than .02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.

Chlordesmethyldiazepam a long-acting benzodiazepine was compared with lorazepam a short-acting one in a double-blind placebo cross-over study against generalized anxiety disorders. Chlordesmethyldiazepam therapy was more effective than lorazepam. Clinical efficacy, drowsiness and insomnia seem well correlated with pharmacokinetic properties of these two benzodiazepines. These results further support the use of a long-acting benzodiazepine rather than a short-acting one as an anti-anxiety agent.

69 patients hospitalized for chronic respiratory diseases and complaining of moderate to severe insomnia were treated with placebo for 2 days, 36 subjects (52.17%) were discarded for their placebo responsiveness. To the remaining patients who suffered from severe insomnia, 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (chlordesmethyldiazepam, 2 mg orally) was administered for 7 consecutive evenings. The onset, duration, quality of sleep and the state on awakening were scored on the basis of patient subjective measurements. High scores of the four considered parameters were obtained during chlordesmethyldiazepam administration. Three treated patients complained of diurnal drowsiness. Results are discussed with regard to methodological problems in the evaluation of hypnotics.

Plasma desmethyldiazepam concentrations were quantitated by a rapid and sensitive technique using electron-capture GLC. Following addition of diazepam as the internal standard, plasma is extracted at physiological pH into benzene-isoamyl alcohol. The extract is evaporated to dryness and reconstituted with toluene-isoamyl alcohol prior to chromatography. Both diazepam and desmethyldiazepam are quantitatively extracted. The variation of identical samples is 5%, and the sensitivity is 5 ng of desmethyldiazepam/ml of original sample. The method is applicable to pharmacokinetic studies of clorazepate, a benzodiazepine derivative transformed to desmethyldiazepam prior to absorption.

The plasma profile of a single oral dose of pinazepam 10 mg was studied in 6 healthy male volunteers, aged 26 to 31 years. The concentrations of the parent compound and of its metabolite in plasma were measured by gas-chromatography. The peak plasma levels of pinazepam was 36.8 +/- 5.1 ng/ml and of N-desmethyldiazepam 150 +/- 13.3 ng/ml. The plasma concentration of the metabolite become higher than that of the parent compound shortly after administration, suggesting that pinazepam acts as a prodrug.

Inhalation anesthetics have been shown to substantially diminish the clearance of several drugs eliminated by hepatic routes. The purpose of the present study was to determine the influence of halothane-oxygen anesthesia on the hepatic metabolism of diazepam and its proximate metabolites in anesthetized rats whose physiologic status was monitored and maintained. The portal vein, femoral artery and bile duct of male Sprague-Dawley rats 370 to 395 g, were cannulated under pentobarbital anesthesia. After a 2-hr recovery period, [14C]diazepam was administered in to the portal vein as a 0.25-mg/kg bolus followed immediately by a 0.25-mg/kg/hr infusion by the same route. After the attainment of steady state, the halothane group (seven rats) received 1% halothane in oxygen whereas the control group (six rats) continued to breathe room air. The diazepam infusion was maintained for an additional 3 hr. Concentrations of diazepam, N-desmethyldiazepam, 4-hydroxyphenyldiazepam and 3-hydroxydiazepam were determined in plasma; these metabolites as well as oxazepam and N-desmethyl-4-hydroxyphenyldiazepam were also determined in bile. Radioactivity in bile was approximately 98% conjugated; radioactivity in plasma was approximately 30% conjugated. Halothane anesthesia caused an increase in the concentrations of diazepam and its metabolites in plasma, but the steady-state ratios of the concentration of the individual metabolites in plasma to diazepam concentration were not changed. The intrinsic clearance of diazepam was decreased by 42%, P less than .01, and the ratio of formation to elimination clearance of the metabolites measured in plasma was not changed. Halothane anesthesia also decreased the excretion rate of 14C into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorodesmethyldiazepam (I) concentrations were followed for 72 h in the plasma of four volunteers given 2 mg of the drug orally. The drug appears to be well absorbed, reaching peak plasma levels of 20--30 ng ml-1 1--2 h after administration; 72 h after administration, plasma concentrations are still measurable (5 ng ml-1). The analytical method involved a single extraction of I from the plasma into benzene followed by centrifugation, evaporation, and gas-chromatographic analysis of the samples.

In 12 healthy volunteers the kinetics and neuropsychological actions of IV diazepam (DZ) (single dose) were studied with and without the presence of its main metabolite N-desmethyldiazepam (NDDZ). Both the maximal plasma concentration and the steepness of the alpha-slope were correlated with variations in the corresponding continuous reaction time (CRT). EEG profiles, CRT and clinical ratings for anxiety and sedation all showed significant changes between the situations with the metabolite present or absent, but no significant correlation could be found with the kinetic pattern of DZ in the two situations. Tolerance to NDDZ did not develop. The results indicate that the presence of the active metabolite changes the pharmacodynamic profile of the parent compound probably by an interaction at the receptor site between DZ and NDDZ. Changes in the spectrum of effects during long-term therapy with DZ may, therefore, partly be explained in this way.

Saliva samples were obtained from 25 hospital inpatients (14 males, 11 females, aged 19 to 79 years) taking diazepam (6 to 45 mg) daily. Despite interindividual variations in pharmacokinetics, a correlation was found between both dose and salivary diazepam concentration (r = 0.54, P less than 0.01) and dose and salivary N-desmethyldiazepam concentration (r = 0.78, P = 0.01). The correlation between the salivary concentration of diazepam and that of its metabolite is good (r = 0.76, P less than 0.01). The slope of this linear regression, 1.58, reflects the relative clearances of the metabolite and parent drug and agrees with the theoretical value, 1.60, obtained by calculation using known plasma pharmacokinetic and protein-binding parameters. There is a weak linear correlation of steady-state salivary benzodiazepine (drug and metabolite) concentration per milligram dose and age (r = 0.37, P less than 0.01).

Dogs, surgically implanted with a chronic gastric fistula, were chronically dosed with N-desmethyldiazepam (32 mg/kg/day) in four divided doses to attain N-desmethyldiazepam plasma levels comparable to those observed in dogs dependent on diazepam (60 mg/kg/day). The time course of N-desmethyldiazepam abstinence was studied, beginning not less than 2 weeks after stabilization levels had been achieved. The abstinence syndrome observed after abrupt discontinuation of N-desmethyldiazepam was similar to the diazepam abstinence syndrome but differed in several important aspects. In diazepam-dependent dogs, there was a short burst of tremor very early in withdrawal (approximately 1-2 hr after the last dose of diazepam) that was not seen in N-desmethyldiazepam-dependent dogs. Signs of abstinence such as tremor, hot foot walking and twitches and jerks were more frequently observed in N-desmethyldiazepam-dependent dogs than in diazepam-dependent dogs as were decreases in food and water intake and in body weight. The overall intensity of abstinence, as measured by the Diazepam Withdrawal Abstinence Scale, was greater in N-desmethyldiazepam-dependent dogs than in dogs dependent on either lorazepam or diazepam. Plasma levels of N-desmethyldiazepam and oxazepam were nearly equal in dogs dependent on diazepam or on N-desmethyldiazepam and were 4 to 10 times greater than the plasma levels of diazepam or lorazepam in diazepam- or lorazepam-dependent dogs, respectively. Furthermore, the plasma levels of N-desmethyldiazepam and oxazepam declined much more slowly than the levels of diazepam and lorazepam. These results suggest that physical dependence on diazepam is caused by the accumulation and actions of N-desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Forty alcohol abusers (with a history of long-time alcohol addiction and mean daily use over 360 grams of alcohol) were treated with tiapride or chlordesmethyldiazepam when stopped their overdrinking. The aim of such pharmacological treatment was both a valuation of effectiveness towards ten target-symptoms and the attempt to avoid the development of a withdrawal syndrome-or, at least, to shorten its course. Chlordesmethyldiazepam resulted to be on the whole more effective than tiapride in dominating all most dramatic symptoms of Delirium Tremens and in avoiding--in a significantly higher number of patients--the onset of a DT syndrome in all its typical features. Moreover, CDDz appeared as a manageable drug and free from important side-effects, and could control symptoms without need of further therapies.

A rapid and sensitive high-performance liquid chromatographic method is described for the quantitative analysis of dipotassium clorazepate (CZP) and its major metabolite nordiazepam (ND) in fresh human and dog plasma. The method consists of two separate selective ND extractions from a plasma sample without and with conversion of all the CZP to ND. For quantitation, diazepam (DZP) is used as the internal standard. The chromatographic phase utilized in a reversed-phase Hibar EC-RT analytical column prepacked with LiChrosolv RP-18 with a solvent system consisting of acetonitrile-0.05 M sodium acetate buffer, pH 5.0 (45:55). The UV absorbance is monitored at 225 nm using a variable-wavelength detector. The mean assay coefficient of variation over a concentration range of 20-400 ng per ml of plasma is less than 3% for the within-day precision. Recoveries of ND, DZP and CZP (as ND) are essentially quantitative at all levels investigated. The calibration curves of ND are rectilinear (r2 = 0.99) from the lower limit of sensitivity (2 ng/ml) to at least 2000 ng/ml in plasma. Applicability of the method to CZP and ND disposition studies in the anaesthetized mongrel dog is illustrated. When the two separate selective nordiazepam extractions from plasma cannot be performed immediately after blood sampling, an extrapolation kinetic method is suggested for the estimation of CZP concentration. In all previous in vivo studies, CZP has been determined only with gas-liquid chromatographic methods.

A combined GLC-ECD and HPLC procedure has been developed for the analysis of the most commonly encountered benzodiazepine drugs and has been applied to both plasma and postmortem blood samples. There is no doubt that since their introduction the use of these sensitive analytical methods have resulted in an increase in the incidence of detection of these drugs in both clinical and forensic toxicology cases.

The nocturnal sleep of eight healthy young volunteers was studied after placebo, Fosazepam 100 mg and Nitrazepam 10 mg. Overall results were very similar after the two drugs. During drug periods there was less of sleep Stages I, III + IV and REM, compensated by an increase in Stage II. The decrease in SWS (III + IV) persisted during the withdrawal periods. There was also an increase in Stage I during Fosazepam withdrawal, whereas the percentage of other sleep stages returned to normal. Sleep quality was reported to be slightly better and morning drowsiness, as well as hangover effects, were said to be less pronounced after Fosazepam than after Nitrazepam.

Chloroquine, monodesethylchloroquine, diazepam, and nordiazepam levels are simultaneously determined in whole blood or plasma by HPLC. Papaverine is used as internal standard, and the analysis is performed after protein-binding hydrolysis, absorption on Extrelut, and elution with diethyl ether/methylene chloride (70:30 v/v). UV detection is used at 343 nm for 12 min, then changed to 242 nm. There are two mobile phases with two flow rates. The procedure requires 30 min, is reproducible, sensitive (8-10 ng/mL for chloroquine and its metabolite, 4 ng/mL for diazepam and nordiazepam), and selective, especially towards other antimalarial agents and drugs like adrenaline or barbiturates, which may be used in chloroquine poisoning therapy. It can be used for pharmacokinetic studies, therapeutic control, to establish the diagnosis and prognosis of a chloroquine poisoning, and to follow and optimize treatment.

A simple, one-step chemical oxidation of triazolam (7) to its 4-hydroxy analogue, 7a, has been developed and applied to other triazolo- and imidazobenzodiazepines. The reaction may be used to convert diazepam to temazepam. 4-Hydroxytriazolo[4,3-a][1,4]benzodiazepines have low central nervous system sedative and anticonvulsant activity in sharp contrast to metabolites of diazepam which remain active. While 10, an alpha-hydroxy metabolite of triazolam, retains much of the activity of 7, 10a, and alpha,4-dihydroxy metabolite of triazolam, is 250 times less potent than 7 on the nicotine-antagonism assay and over 300 times less potent on the traction assay.

The pharmacokinetics of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) in both plasma and brain after a single 5 mg/kg IP dose of diazepam were studied in rats. Four rats were sacrificed at 5 min, 15 min, 30 min, 1 h, 1.5, 2, 3, 4, 5 and 6 h after the dose. DZ rapidly disappeared from plasma and brain in parallel, with nearly identical overall half-lives of 0.88 and 0.89 h, respectively. Apparent volume of distribution was 19.3 1/kg and the apparent total clearance was 255 ml/kg/min. Free fractions were 19.6% and 15.8% for DZ and DMDZ, respectively. DMDZ rapidly appeared in both plasma and brain. Thereafter, DMDZ was likewise eliminated in parallel from both compartments, with nearly identical half-lives of disappearance from plasma (1.11 h) and brain (1.09 h). The rapid elimination of DZ was due to its very high clearance. Brain to plasma concentration ratios did not differ significantly over time either for DZ or for DMDZ. The overall ratios (mean +/- SE) were 4.5 +/- 0.1 for DZ and 3.5 +/- 0.2 for DMDZ. Equilibrium was attained at no more than 5 min after dose for both DZ and DMDZ. No evidence was found for persistence or sequestration of DZ or DMDZ in brain longer than could be predicted on the basis of first-order exponential disappearance.

A rapid gas-liquid chromatographic technique has been developed for use in the simultaneous measurement of both diazepam and its major metabolite, desmethyldiazepam, in blood plasma. Neither solvent transfer nor evaporation steps are required in this procedure. Extremely small plasma volumes (20 to 100 microleter) are used and this has proved advantageous, especially when analysing samples from neonates. A linear response to amounts from 1-10(-12) to 1-10(-9) g/sec of both diazepam and desmethyldiazepam has been obtained and thus the direct analyses of these compounds both during therapy and after overdosage has been possible. Interference from either endogenous or exogenous sources has been found to be minimal.

Eight normal subjects were tested on a battery of subjective and psychological tests 12 hours after a hypnotic dose of chlordesmethyldiazepam (1 or 2 mg), amylobarbitone sodium (100 mg), and a placebo. The tests included self-ratings of hypnotic effects and alertness; reactiontime, card-sorting, coding and cancellation tasks; arithmetic; and tapping. Before each task, test anxiety and performance expectation was self-rated; and after the task, judgment of performance was self-rated. Residual effects were definitely detectable after the 2-mg dose of benzodiazepine with both behavioral impairment and subjective hangover. Both the 1-mg dose and the barbiturate were almost devoid of such effects. Very few drug effects on test anxiety and performance judgment were discerned. Plasma concentrations of amylobarbitone were related to decreases in test anxiety and of chlordesmethyldiazepam with ratings of sleepiness.

The influence of propranolol coadministration or of cigarette smoking on the kinetics of desmethyldiazepam following a single 20-mg intravenous dose of clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous clorazepate was given once in the control condition, and again during coadministration of propranolol, 80 mg twice daily. Compliance with the prescribed propranolol regimen was verified by measurement of serum propranolol concentrations (mean, 37 ng/ml). In control vs propranolol treatment conditions, there was no significant difference in desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of desmethyldiazepam half-life (55 vs 61 h, P less than 0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg, P less than 0.02) attributable to propranolol. In Study Two, desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and body weight. There was no significant difference between controls and cigarette smokers in desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus, propranolol slightly although significantly impairs the clearance of desmethyldiazepam and prolongs its half-life. Cigarette smoking has no apparent influence on desmethyldiazepam kinetics.

A rapid procedure for the measurement of serum diazepam (D), N-desmethyldiazepam (ND), and N-desalkylflurazepam (NF), levels in clinical samples is described. The single step extraction procedure yields quantitative extraction for the drugs mentioned above. No solvent evaporation step is needed. No interference of endogenous substances or generally used psychotropic drugs containing halogen atoms has been observed. The conditions provide excellent precision, due to a clear separation of the internal standard, medazepam, from the solvent front. The frequency response electron capture detector provides a linear response to the drugs over a 5 X 10(2) concentration range making serial dilution of the samples unnecessary. The automatic data reduction system indicates the serum levels directly in ng/ml without manual calculations.

N-Desmethyldiazepam in plasma has been determined by gas chromatography with electron capture detection, using N-desmethyltetrazepam as internal standard and a column filled Poly-A 103 on Gas-Chrom Q. No prior transformation of benzodiazepines is necessary. The sensitivity is ca.1 ng/ml and the recovery is greater than or equal to 70%. The method is particularly suitable for the pharmacokinetic study of dipotassium clorazepate: the amount of unchanged clorazepate may be estimated from the difference between the amount of N-desmethyldiazepam present initially and the total amount of N-desmethyldiazepam obtained after acidic treatment of the sample; the method is also useful for therapeutic control and for analytical toxicology.

24 patients, ages ranging from 6 months to 14.5 years, affected by epilepsy resistant to common antiepileptic drugs were studied. CDDZ was administered intravenously at doses from 0.5 to 2 mg and EEG was recorded for 45 min (15 min before and 30 after drug administration). In 20 patients the EEGraphic paroxystic activity was modified: in 5 cases a total remission and in 2 cases a partial remission were obtained; in 13 cases the EEG alterations were reduced. Myoclonic petit mal and organic focal seizures were the forms of epilepsy showing the best responses to CDDZ administration. The drug was well tolerated and only in two cases was persistent drowsiness observed for more than six hours, possibly due to concomitant barbiturate therapy.

1 Hospitalized patients suffering from insomnia were treated with N-demethyldiazepam (30 mg p.o.) for 10 days, while continuing treatment with nortriptyline (75 or 100 mg daily). 2 Clinical evaluation performed by objective rating scales showed a positive therapeutic effect. No correlation was found however between drug plasma levels and clinical efficacy. A high inter-individual variability was observed. 3 In three cases the N-demethyldiazepam disappearance curve showed a biexponential decay, with a slow first component followed by a faster one. 4 Compared with diazepam the tested drug has a longer plasma apparent half-life and a lower relative clearance.

It has been reported that hypovolemia secondary to extensive blood loss alters the functionality of the central nervous system and is associated with changes in the dose requirements or intensity of action of various central nervous system depressants, including a benzodiazepine. To investigate the mechanism(s) of this effect, the influence of experimental hypovolemia on the pharmacodynamics, receptor binding and pharmacokinetics of a benzodiazepine drug was determined. Adult male Sprague-Dawley rats were made hypovolemic by removal of about 30% of their blood over 30 min. An i.v. infusion of desmethyldiazepam (DDZP) was started 30 min later and continued until the animals lost their righting reflex. Compared to results obtained with normal controls, the hypovolemic rats required about one-half the dose of DDZP to produce loss of righting reflex and had significantly lower DDZP concentrations in serum and cerebrospinal fluid at that time. This effect of substantial blood removal could not be reversed by prompt return of the removed blood to the animals. Experimental hypovolemia had no apparent effect on the in vitro binding of tritiated diazepam to benzodiazepine receptor sites in the cerebral cortex of rats. The plasma clearance of DDZP was decreased significantly and the biological half-life was increased in hypovolemic rats compared to normal animals when both received a 30-mg/kg dose by i.v. infusion over 10 min. It is concluded that acute hemorrhagic hypovolemia increases the sensitivity of the central nervous system to the depressant effect of DDZP and decreases the body clearance of that drug in rats. Thus, the pharmacodynamics as well as the pharmacokinetics of a benzodiazepine are altered by hypovolemia.

Halazepam and its major metabolite desmethyldiazepam (DMDZ) can be reliably quantitated in human plasma following single doses of halazepam. After addition of appropriate internal standards, halazepam and DMDZ are extracted directly into an organic solvent at physiological pH. The organic extract is separated, evaporated to dryness, reconstituted, and directly chromatographed using a 50:50 methyl:phenyl silicone column (SP-2250) and an electron-capture detector. After a single 40 mg oral dose of halazepam, the parent compound appears in plasma only transiently and at low levels. DMDZ appears in higher concentrations and is slowly eliminated. During multiple-dose therapy with halazepam, DMDZ will be the major active substance in blood.

Electron-capture gas-liquid chromatography was used for simultaneous quantitation of plasma diazepam (I) and its major metabolite, desmethyldiazepam(II). Because concentrations of I can greatly exceed those of II after single doses of I, two benzodiazepine-analog internal standards were added to all samples, thereby allowing reliable quantitation of high concentrations of I and low concentrations of II. After extraction at neutral pH with benzene (containing isoamyl alcohol), the organic extract is evaporated and the residue is reconstituted in a small volume of solvent and chromatographed on a 3% OV-17 column. The sensitivity limits are 2 to 3 ng of I or II per milliliter of original sample, with a CV for identical samples of less than 5%. The applicability of the method to single-dose pharmacokinetic studies of I in humans is illustrated.

Following administration of chlordiazepoxide HCl to man, N-desmethyldiazepam, a known metabolite of diazepam (Valium), was identified in plasma. The metabolite was identified on the basis of its thin-layer chromatographic (TLC) mobility, electron-capture gas-chromatographic (EC-GC) retention time, and mass spectrum relative to authentic N-desmethyldiazepam. Plasma levels of N-desmethyldiazepam in subjects receiving both single and chronic doses of chlordiazepoxide were determined by an EC-GC method with a limit of sensitivity of 10 ng/ml using 2-ml samples and by a radioimmunoassay procedure which had a limit of sensitivity of 20 ng/ml using a 0.1-ml sample. Both assay methods gave good agreement for the levels of N-desmethyldiazepam. In subjects receiving a single 30-mg oral or intravenous dose of chlordiazepoxide, measurable levels of N-desmethyldiazepam in plasma (10 to 60 ng/ml) were obtained 24 to 72 hr after administration. In 5 subjects receiving 10 mg of chlordiazepoxide three times a day, steady-state levels of N-desmethyldiazepam in plasma were reached after about 1 wk of administration. The mean maximum and minimum steady-state levels of N-desmethyldiazepam were 260 and 220 ng/ml of plasma, respectively. Similar steady-state levels were observed on treatment with 30 mg of chlordiazepoxide over 24 hr.

A new benzodiazepine, chlordesmethyldiazepam, was administered at a dose of 6 mg/day to 27 patients (18 neurotics and 9 psychotics) with the common symptom of anxiety. The study period was limited to eight days for the whole group, although the drug has been given to some patients for 38 days. Changes in global scores in neurotic patients were determined by administering the Wittenborn and Hamilton rating scales. In psychotic patients the same rating scales were used in addition to the BPRS. A multistimulator was used to evaluate the performance recording complex reaction times (CRT). The statistical evaluation of results shows a highly significant amelioration of all the studied parameters except for reaction times in the psychotic group.