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A total of 45 patients with generalized anxiety disorder were treated twice daily for 2 weeks, on a double-blind basis, with 0.5 mg etizolam, 0.5 mg alprazolam or 3 mg bromazepam, and symptoms were assessed using Hamilton's rating scale for anxiety and Hamilton's rating scale for depression. Patients then received the same drug for a further 2 weeks, the drugs being given three times daily if a poor response was observed during the first 2 weeks. All drugs displayed equivalent anxiolytic activity after 2 weeks, but etizolam displayed a progressive increase in anxiolytic activity over 4 weeks of treatment. Etizolam also possessed a more marked antidepressant effect than did alprazolam or bromazepam. There were no differences in the tolerability of the three drugs.

Plasma concentrations of desmethyldiazepam (DMDZ) and intensity of self-rated sedation (SRS) were measured at multiple points in time during 6 h after a single 15 mg oral dose of clorazepate dipotassium. Mean plasma DMDZ levels and mean SRS scores both became maximal at 1.0--2.5 h after drug dosage. By 6 h, however, mean SRS had returned to the predrug baseline score while mean DMDZ concentration fell only slighty from the maximum value. Disappearance of SRS despite persistence of high DMDZ levels might be due to adaptation or tolerance. If this is the case, subjective effects of benzodiazepines may depend upon duration of drug exposure as well as dose and concentration.

Ten milligrams of diazepam were injected intraamniotically in 8 mothers prior to therapeutic abortion between 12 and 19 weeks. The diazepam concentrations in the maternal plasma were comparable to those found after the same intramuscular diazepam dose to the mother. The concentration of diazepam in the amniotic fluid 12 to 18 hours after the injection was no longer significantly higher than in the maternal plasma. The concentrations of diazepam in the fetal plasma, liver and brain were comparable to the concentrations resulting from a 10 mg intramuscular diazepam dose to the mother about 2 hours before legal abortion. The feto-maternal ratio of diazepam was of same magnitude as after the intramuscular application to the mother. The results indicate that the disappearance of diazepam from the amniotic fluid in this stage of pregnancy occurs extraplacentally, through the mambranes into the uterine circulation. In the treatment of a fetus with drugs having properties similar to diazepam, intra-amniotic administration is no better than intramuscular administration to the mother.

A double-blind, randomized protocol was used to investigate the activity of a benzodiazepine derivative, chlordesmethyldiazepam, at two different dosages, 1 mg and 2 mg (CDDZ1 and CDDZ2), on mnestic functions and information processing in normal subjects. CDDZ2 significantly impaired short-term shortage of logical and associative memory, without activity on spatial and visual memory, whereas CDDZ1 showed no difference from the placebo. Neither CDDZ1 nor CDDZ2 impaired the level of vigilance and the information processes the morning after use of the drug.

The effectiveness of 30 mg temazepam (SaH 47-603) for inducing and maintaining sleep was evaluated in the sleep laboratory in six insomniac subjects under conditions of short-, intermediate-, and long-term drug administration. Administration of temazepam had no effect on sleep induction. In addition, effectiveness was not demonstrated for sleep maintenance: wake time after sleep onset was not significantly decreased on any of the three drug conditions, while the number of nightly awakenings was significantly decreased on all three drug conditions. Total wake time was decreased only slightly with short-term drug administration and was similar to baseline with intermediate- and long-term use. The percent REM sleep was essentially unchanged throughout the drug administration period. On the initial set of withdrawal nights, the per cent REM sleep was slightly but no significantly increased over baseline. The per cent slow wave sleep decreased significantly with short-, intermediate-, and long-term drug administration. After withdrawal, the percent slow wave sleep returned to baseline values.

The aim of this investigation was to study whether and to what extent 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (diazepam, Valium) passes into the breast milk during repeated oral administration to nursing mothers. It was shown that diazepam and its main and also active metabolite desmethyldiazepam passed into the milk. Their concentrations, however, remained small as compared to plasma values. Desmethyldiazepam levels in the milk were consistently higher than those of diazepam. These results are explained by the relative binding of both substances to plasma proteins. The maximum quantities of diazepam + desmethyldiazepam that can possibly be absorbed by a newborn with the milk of a mother receiving 10 mg Valium daily, are considered to be too small to cause any untoward effects in the baby. If, however, high doses of Valium must be administered repeatedly, breast-feeding should be discontinued for safety reasons.

Dose-response profiles were determined for chlordiazepoxide, diazepam and N-desmethyldiazepam in a squirrel monkey punishment (conflict) procedure. The monkeys were trained to lever press under a food-maintained concurrent schedule consisting of an unpunished 6-minute variable interval (VI) schedule, and a 1.5-minute VI schedule, on which responses were punished intermittently (24 response variable ratio) with electric footshocks. The three benzodiazepines effectively increased responding that had been suppressed by punishment; they had inverted U-shaped dose-effect curves. The minimum effective doses for increasing punished responding were: diazepam less than or equal to 0.31 mg/kg p.o.; N-desmethyldiazepam = chlordiazepoxide = 0.62 mg/kg. As a model to assess potential antianxiety activity, this procedure possessed excellent sensitivity and reliability. The following observations were also made. 1) During initial training, as shock intensity was increased and punished responding became suppressed, some monkeys exhibited an increase in unpunished response rates. This may have represented "positive behavioral contrast," but response rate changes were associated with changes in the amount of time the monkeys allocated to each schedule. 2) At certain dose levels, all three compounds exerted antipunishment effects 24 hours after administration. 3) As was reported previously for rats, when the monkeys had no previous drug experience ("drug-naive") they were more sensitive to the depressant effects of the benzodiazepines. With repeated administration, there was a reduction in this sedation and a concomitant increase in the antipunishment effect. This phenomenon was dose- and animal-dependent.

1 The immediate and residual effects on performance of benzodiazepines differ, and the differences are important in the use of these drugs. 2. Diazepam and its hydroxylated metabolites, temazepam and oxazepam, each possess hypnotic activity, and have effects on performance limited to the sleep period. The demethylated metabolite of diazepam, nordiazepam, and its precursor, potassium clorazepate, which also possess hypnotic activity, have a longer duration of action, although the next day anxiolytic effect is accompanied by only minimal effects on performance. The 1.5 benzodiazepine, clobazam, seems to have minimal immediate effects on performance. 3 Diazepam and its hydroxylated metabolites, temazepam and oxazepam, would be useful in the management of insomnia without psychopathology in those cases in which residual effects on performance must be avoided. Nordiazepam and potassium clorazepate would be appropriate for insomnia secondary to day-time anxiety, and clobazam may be useful as a day-time anxiolytic. 4 It is emphasized that more work needs to be carried out on the effects of anxiolytics on performance before one can be certain that ingestion during the day would be without any deleterious effects on skilled work.

Plasma levels of diazepam and N-desmethyldiazepam were investigated in 19 children by a gas chromatographic method permitting the use of capillary sample. Intravenous administration was studied in 3 children and the plasma level curves showed a rapid decline during the first hour. Absorption and elimination after rectal administration of a solution in 16 children were similar to those after intramuscular administration. Diazepam given by suppository to 5 children gave much lower plasma levels and delayed time to peak levels. Recurrence of seizures in 2 children indicated that the anticonvulsants plasma level was of the order of 150 to 200 mug/liter. No significant side effects were observed. Thus rectal administration of a solution of diazepam is a practical method to arrest convulsions in children.

Desmethyldiazepam pharmacokinetics were determined after oral administration of its precursor, clorazepate, to 12 obese subjects (mean weight: 105.4 kg; mean percent ideal body weight: 170%) who were matched for age, sex, and smoking habits with 12 normal controls (66.5 kg; percent ideal body weight: 103.3%). After an overnight fast, a single 15-mg clorazepate capsule, equivalent to 10.3 mg of desmethyldiazepam, was administered. Multiple plasma samples drawn 10-42 days postdose were analyzed for desmethyldiazepam by electron-capture GLC. Obese subjects compared to controls had a prolonged desmethyldiazepam elimination half-life (t1/2) (154.1 hr versus 57.1 hr; p less than 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (Vd) was greatly increased in the obese (158.8 liters versus 63.3 liters; p less than 0.001). The value of Vd remained greater even after correction for body weight (1.52 liter/kg versus 0.94 liter/kg; p less than 0.005). However, clearance of desmethyldiazepam was not different between groups (13.2 ml/min in obese versus 13.4 ml/min in controls). The percent ideal body weight was highly correlated with Vd (r = 0.82), as was total body weight (r = 0.86). The value of t1/2 was correlated highly with Vd (r = 0.89) but only weakly with clearance (r = -0.38). Therefore, the large increase in the desmethyldiazepam t1/2 value seen in obese subjects is predominantly due to the disproportionate distribution of this lipid-soluble drug into body fat as opposed to lean tissue. The contribution of clearance to desmethyldiazepam t1/2 was of much less importance than was Vd in this obese study population.

1 Plasma concentrations of diazepam and its metabolite, desmethyldiazepam, have been measured in both in- and out-patient groups treated with diazepam for periods varying between 1 month and 10 years. 2 The diazepam concentration was directly related to the dose of diazepam ingested and inversely related to the age of the patient. 3 A highly significant relationship was obtained between the concentration of desmethyldiazepam and diazepam. 4 The plasma concentrations of both diazepam and its metabolite were independent of sex, duration fo therapy and patient group.

Chloro-N-desmethyldiazepam (CDD) significantly reduced plasma tryptophan (TRY) and increased brain TRY in mice and rats. Quipazine did not change TRY levels in mouse plasma and brain but it respectively reduced and increased these two parameters in rats, to almost the same extent as CDD. Metergoline, an antagonist of serotonergic receptors, decreased blood TRY in both mice and rats but failed to change brain TRY. CDD significantly but slightly increased brain serotonin in rats. This effect was blocked by metergoline.

High-performance liquid chromatography, UV spectrometry and mass spectrometry have established that tablets of sibazon and seduxen contained equal quantities of pharmacologically active component diazepam. Radioligand assays revealed the diazepam blood serum levels twice as high 30 to 45 min after oral administration of seduxen than those after sibazon intake (p. less than 0.05). These differences were no more detectable after 2 to 3 hours. The pharmacokinetic differences could be accounted for by the properties of constituents.

Efficacy and side effects of flurazepam 15 mg, fosazepam 60 mg, and nitrazepam 5 mg were studied in 17 psychogeriatric patients. The drugs were equipotent in maintaining sleep but nitrazepam had more side effects than the other hypnotics, and it induced a rebound insomnia after withdrawal. All hypnotics lost some of their efficacy towards the end of 7 days' administration. Patients with evident cerebrovascular disease were vulnerable to the side effects of the benzodiazepine hypnotics. The side effects did not correlate with the age of a patient. In addition, no correlations were found between the serum levels of fosazepam or its main metabolite and the side effects.

In 11 preoperative women, plasma adrenaline (A) concentrations were lower after oral administration of an antianxiety dose (19.25 micrograms/kg) of chlordemethyldiazepam (Cl-DMDZ) than the predrug values, or those in 12 patients given placebo. No significant differences in supine plasma noradrenaline (NA), blood pressure (BP) and heart rate values were observed. Digital plethysmography showed finger vasoconstriction after placebo and vasodilatation after Cl-DMDZ. A mental arithmetic test caused equivalent rises in plasma A in both groups. Standing caused plasma NA to rise to similar levels in both groups of patients, but the BP decrease was less and there was a markedly lower incidence of orthostatic hypotension in the Cl-DMDZ treated group. It is concluded that the effect of Cl-DMDZ on the release of catecholamines from the peripheral sympathetic system consists essentially of decreasing basal adrenomedullary activity. CL-DMDZ appears to prevent the orthostatic hypotension which occurs when neurosympathetic reflex activation is normal.

Placental transfer of pinazepam and its metabolite N-desmethyldiazepam was investigated in 25 pregnant women at term. Pinazepam was administered orally as a single (10 mg) dose to 13 women, or in multiple doses of 5 mg daily to 12 women. The dose-delivery interval ranged between 1 and 26 h for the single dose, and the period between the last of the multiple doses and delivery was 1.4 to 24 h. Pinazepam and N-desmethyldiazepam were measured in plasma obtained from the umbilical vein and from the mother, at delivery. Pinazepam was only detectable in plasma after the 10 mg dose. The drug did not reach an apparent equilibrium between fetal and maternal plasma. The average (+/- SEM) cord/maternal ratio of plasma pinazepam concentrations was 0.64 +/- 0.07. N-desmethyldiazepam was detectable on each occasion. Its concentration in the plasma from the cord vein became higher than that in the maternal specimens 1-2 h after administration of the parent drug. Little N-desmethyldiazepam was excreted in breast milk.

Benzodiazepines are known to reduce increased muscle stretch reflexes. To investigate the relationship between the necessary plasma concentrations of diazepam and its major metabolite desmethyldiazepam on the one hand and the phasic and tonic ankle reflex activity on the other, 10 mg diazepam was given intravenously to nine patients, seven with spasticity due to multiple sclerosis and two with parkinsonian rigidity. Diazepam and desmethyldiazepam both had a normalizing effect on the increased phasic ankle reflex seen in spasticity. No effect was observed on the increased tonic reflexes in rigidity. The concentrations of diazepam necessary to reduce spasticity ranged between 300-2,200 mg/l and were so high that drowsiness did occur. However, the study may indicate that desmethyldiazepam has a higher potency and a more long lasting effect on the increased phasic reflexes than diazepam.

The plasma protein binding of diazepam and of its main metabolite, N-demethyldiazepam, was measured in patients with renal disease and in healthy volunteers by ultracentrifugation. The total and non-protein bound concentrations of diazepam and N-demethyldiazepam, and the concentration of unconjugated oxazepam in the plasma were determined by gas chromatography after an oral 10 mg dose of diazepam. In the volunteers 98% of diazepam and N-demethyldiazepam were bound to the plasma proteins. In patients with renal disease the corresponding values were 92% and 95%, respectively. In the patients with renal disease no correlation could be found between the percent protein binding of diazepam or N-demethyldiazepam in the plasma and the serum creatinine concentration. Considerable variations in diazepam concentrations at 1 and 24 hours and in N-demethyldiazepam concentrations at 24 hours were found in the patients with renal disease. In contrast to the volunteers, 5 patients out of 28 with renal disease had measurable amounts of unconjugated oxazepam in the plasma. The deficient ability of the plasma proteins of patients with renal disease to bind diazepam may increase its clinical effect.

The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21--66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.

Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t1/2 a) averaged 24 min. Neither peak time nor t1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t1/2 beta) of 82 h (range 27-219 h). t1/2 beta became prolonged with age in men but not in women. Likewise, clearance of total (free bound) DMDZ declined with age in male subjects (r=- 0.47, P less than 0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0-4.3%), and increased significantly with declining plasma albumin concentrations (r=-0.57, P less than 0.001). Partly due to a decline in plasma albumin with age (r=-0.47, P less than 0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=-0.65, P less than 0.01), but actually was slightly higher in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.

Dihydrodiazepam is a diazepam prodrug, as shown by its in vitro metabolism by rat and mouse liver and brain microsomal fractions, and its displacing activity on brain diazepam binding. The mechanism of bioactivation is discussed. Stereoselectivity of metabolism and of binding to specific benzodiazepine binding sites in brain synpatosomes and serum albumin were studied.

Five dogs received a single 1.0 mg/kg dose of diazepam (DZ) IV. Concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were simultaneously measured in plasma and cisternal cerebrospinal fluid (CSF) for up to 8 h after the dose by electron-capture gas-liquid chromatography. DZ was rapidly eliminated from plasma (half-life 0.3--1.3 h); DZ disappearance was mirrored by formation of DMDZ, which in turn was eliminated slowly, Both DZ and DMDZ rapidly penetrated CSF and concentrations in CSF declined parallel with those in plasma. Despite rapid uptake, the extent of CSF transfer of DZ and DMDZ was limited by plasma protein binding. Mean CSF:plasma concentrtion ratios for DZ (range 0.023--0.137) and DMDZ (range 0.047--0.119) were highly correlated with the unbound fraction in plasma (r = 0.95 and 0.80, respectively). Thus DZ and DMDZ concentrations in CSF, presumed to reflect concentrations at the site of action, are determined by unbound plasma concentrations. The intensity of pharmacologic action is more likely to correlate with unbound than with total plasma concentrations.

Total serum benzodiazepine concentrations were correlated with clinical manifestations in 93 cases of diazepam overdose. Diazepam and nordiazepam were also each separately determined in 101 serum specimens from cases of diazepam overdose, including 27 cases from the aforementioned clinical correlation study. In addition, serum nordiazepam concentrations were measured in five cases of chlorazepate overdose. Concentrations of total benzodiazepine ranged from 1 to 22 microgram/ml. All patients survived with supportive therapy only. Each of the 25 patients who had ingested only diazepam was awake or in grade 0 coma, even when drug concentrations were ten-fold greater than the accepted upper limit of the therapeutic range. None of the patients who had ingested only diazepam needed hospitalization; all were discharged from acute medical care after a period of emergency room observation. The ratios of parent drug to N-desmethyl metabolite (nordiazepam) in those overdose specimens analyzed by gas chromatography averaged 3:1. This high ratio may be useful in differentiating acute overdose from high concentrations resulting from chronic therapy. Although determination of diazepam concentrations aid in establishing that an overdose has occurred, when more than grade I or II coma is present, other drugs or an alternative explanation should be sought, regardless of the drug concentration.

An endogenous brain substance that binds to the central-type benzodiazepine receptors with agonist properties is present in both rat and bovine brains. This substance has been purified to homogeneity from bovine brain by immunoaffinity chromatography on immobilized monoclonal anti-benzodiazepine antibody followed by gel filtration on Sephadex G-25 and two reversed-phase HPLC steps. The purified substance was characterized as the benzodiazepine N-desmethyldiazepam (nordiazepam). The techniques used for the identification were mass spectrometry, HPLC, spectrophotometry, benzodiazepine receptor binding, and immunological techniques. Benzodiazepine-like immunoreactivity was also found in all the human brains tested, including six brains that had been stored in paraffin since 1940, fifteen years before the first synthesis of benzodiazepines. These results show that benzodiazepine-like molecules of natural origin--and possibly benzodiazepines themselves--are present in human and other mammalian brains.

Clorazepate 20 mg was given i.m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. "Total nordiazepam", i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.

The kinetics of a single 1-mg oral dose of chlordemethyldiazepam (CDDZ, En) was determined on two occasions in 8 healthy volunteers. CDDZ was given in the fasting state on one occasion and following a standard meal on another. Compared with the fasting state, administration of CDDZ with food prolonged the time to reach peak concentration (1.5 vs. 6.8 h after dosage, p less than 0.01) and the absorption half-life (28 vs. 231 min, p less than 0.01). Total area under the curve was not influenced, nor was CDDZ elimination half-life (84.2 vs. 88.7 h). Thus administration of CDDZ with food slows the rate of its absorption but does not alter the completeness of absorption.

A sub-chronic study of 7-chloro-2,3-dihydro-3-hydroxy-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (temazepam, Euhypnos) at three dose levels was carried out in 30 healthy volunteers. A matching placebo was given before and after the 4 nights of active compound. The subjective response was measured by means of a sleep evaluation questionnaire, and the objective measurements used were the critical flicker fusion threshold and choice reaction time. A clear dose-response relationship was seen in the subjective and objective measurements with the three doses used. A rebound phenomenon was seen only at the high dose levels in two subjective measures, viz. getting to sleep and behaviour following waking.

The pharmacological profile of chlordesmethyldiazepam was studied in mice and compared with that of other benzodiazepines (diazepam, lorazepam, clonazepam, nitrazepam, oxazepam, flunitrazepam, medazepam and chlordiazepoxide). All the drugs were administered perorally and their anticonvulsive activity (antagonism towards pentetrazole-induced clonic convulsions), anxiolytic action (the four-plate test), myorelaxant activity (the rota-rod test), sedative effect (inhibition of the locomotor activity) and neurotoxic effect (abolition of the righting reflex) were estimated. Chlordesmethyldiazepam revealed an anticonvulsive action (ED50 = 0.11 mg/kg), anxiolytic activity (MED = 2 mg/kg), myorelaxant action (ED50 = 17.5 mg/kg), sedative effect (ED50 = 34 mg/kg) and neurotoxic action (NTD50 = 190 mg/kg). Considering the potency of action (ED50) in respective tests and the therapeutic indices (NTD50/ED50 ratio), chlordesmethyldiazepam in respect of its profile resembles most lorazepam and diazepam.

The relationship between the dose and anxiolytic effects of diazepam and the serum concentrations of diazepam and nordiazepam were examined in groups of acutely and chronically anxious patients. The results showed a significant correlation between dose and serum nordiazepam concentrations after short-term (14-day) administration, but no significant association between clinical symptoms of anxiety and serum diazepam and nordiazepam. We conclude that the main value of serum benzodiazepine measurements in anxious patients in assessing compliance, particularly in patients suspected of taking more than the recommended dose. Serum nordiazepam is a more consistent index of dosage after chronic therapy than serum diazepam because it has a longer elimination half-time.

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

The protein binding of diazepam, desmethyldiazepam, furosemide, indomethacin, warfarin, and phenobarbital in maternal and fetal cord serum at the time of birth, and in serum of neonates between 1 and 11 days of age was studied. The protein binding of diazepam and desmethyldiazepam was higher in the fetus than in the mother, thus explaining the fetal cumulation of these drugs in vivo. After birth, both drugs were partially displaced from neonatal binding sites. The decreased protein binding capacity in the mother and the neonate related to increased free fatty-acid levels. The pattern of protein binding of warfarin in the groups investigated was a mirror image of those of diazepam and its metabolite. The protein binding of indomethacin progressively decreased in the neonate during the first two postnatal weeks, while that of furosemide remained at lowered levels throughout this time interval. The protein binding of phenobarbital was similar in the groups investigated. Our results suggest that drugs such as diazepam, which can be displaced from binding sites by free fatty acids, may cumulate in the fetus and may exhibit much decreased protein binding and possibly unexpectedly strong effects in the neonate after birth.

The pharmacokinetics of a single intravenous dose of diazepam 0.1 mg/kg was studied in 6 healthy volunteers, in random order under controlled conditions and following pretreatment with its major metabolite, desmethyldiazepam (20 mg/kg/day) for one week. In the two subjects with the highest plasma concentration of desmethyldiazepam (990 and 1100 ng/ml, respectively), total plasma clearance (Cl) of diazepam was reduced after desmethyldiazepam, by 31% and 54%, respectively. In three individuals there was a moderate decrease of 14% to 21%, and no effect was seen in one volunteer. Cl was significantly reduced (11.5 +/- 1.8 vs. 9.1 +/- 3.3 ml/min; p = 0.015) and elimination half-life tended to be prolonged (38.5 +/- 10.4 vs. 65.8 +/- 67.1 h; p = 0.15). It is concluded that high concentrations of desmethyldiazepam can influence the elimination of its parent drug diazepam by product inhibition.

Pinazepam (P) (10 mg) was orally administered to two young (22-23 years) and two elderly (74-80 years) healthy volunteers. Also, desmethyldiazepam (DD) (10 mg) was orally administered to the same young volunteers on a separate occasion. P was almost completely converted into DD 24 h after administration. Plasma levels of DD were measured in all subjects. In all cases, the DD concentration-time curve showed a biphasic decay (a first slow decay was followed by a fast one) which closely fitted by a Michaelis-Menten equation. Vmax and km constant were computed for all subjects. The kinetic analysis relative to the young subjects showed that T 1/2 of both the slow and fast decay as well as the area under the curve (AUC) were reduced when P was administered instead of DD. Comparison of DD kinetics between young and elderly subjects showed an increase of half-life in the elderly, while AUC was found unchanged.

A simple and sensitive method for determination of benzodiazepines in plasma has been developed using high-performance liquid chromatography in a reverse-phase mode. The method is illustrated by application to plasma samples containing diazepam and N-desmethyldiazepam at concentrations which would be encountered during therapy, with limits of detection of 10 ng/ml and 2 ng/ml for diazepam and N-desmethyldiazepam, respectively.

1 Salivary and plasma diazepam and nordiazepam concentrations were measured in 51 paired samples from four experimental situations. In seven of the patients CSF samples were estimated. 2 Correlation of 0.89 (P less than 0.001) was observed between salivary and plasma diazepam and 0.81 (P less than 0.001) between salivary and plasma nordiazepam. 3 Mean salivary diazepam was 1.6% (+/- 0.3%) of the plasma diazepam. It was found to vary markedly in an acute dosage study. Mean salivary nordiazepam was 2.9% (+/- 1%) of the plasma measure and was dependent on salivary flow rate. 4 CSF diazepam was in equilibrium with unbound plasma diazepam and salivary diazepam. 5 Mean protein binding of diazepam in vitro was 99.3% with no variations as a function of concentration. 6 The results suggest salivary diazepam and nordiazepam measures to be of value in epidemiological studies. However, they do not predict accurately the plasma total or unbound drug concentration from a salivary sample in an individual.